US 2006O134109A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0134109 A1 Gaitanaris et al. (43) Pub. Date: Jun. 22, 2006

(54) GPROTEIN COUPLED RECEPTORS AND in-part of application No. 60/461.329, filed on Apr. 9. USES THEREOF 2003.

(75) Inventors: George A. Gaitanaris, Seattle, WA Publication Classification (US); John E. Bergmann, Mercer Island, WA (US); Alexander Gragerov, (51) Int. Cl. Seattle, WA (US); John Hohmann, La CI2O I/68 (2006.01) Conner, WA (US); Fusheng Li, Seattle, C7H 2L/04 (2006.01) WA (US); Linda Madisen, Seattle, WA (US); Kellie L. McIlwain, Renton, WA CI2P 2/06 (2006.01) (US); Maria N. Pavlova, Seattle, WA A 6LX 39/395 (2006.01) (US); Demitri Vassilatis, Seattle, WA C07K I4/705 (2006.01) (US); Hongkui Zeng, Shoreline, WA (52) U.S. Cl...... 424/143.1: 435/6: 435/69.1; 435/320.1; 435/325; 530/350; (US) 536/23.5 Correspondence Address: SEED INTELLECTUAL PROPERTY LAW GROUP PLLC (57) ABSTRACT 701 FIFTHAVE SUTE 63OO The present invention provides GPCR polypeptides and SEATTLE, WA 98104-7092 (US) polynucleotides, recombinant materials, and transgenic (73) Assignee: Nura Inc., Seattle, WA (US) mice, as well as methods for their production. The polypep tides and polynucleotides are useful, for example, in meth (21) Appl. No.: 10/527,265 ods of diagnosis and treatment of diseases and disorders. The invention also provides methods for identifying com (22) PCT Fed: Sep. 9, 2003 pounds (e.g., agonists or antagonists) using the GPCR polypeptides and polynucleotides of the invention, and for (86) PCT No.: PCT/USO3/28226 treating conditions associated with GPCR dysfunction with the GPCR polypeptides, polynucleotides, or identified com Related U.S. Application Data pounds. The invention also provides diagnostic assays for (63) Continuation-in-part of application No. 60/409,303, detecting diseases or disorders associated with inappropriate filed on Sep. 9, 2002, and which is a continuation GPCR activity or levels. Patent Application Publication Jun. 22, 2006 Sheet 1 of 9 US 2006/0134109 A1

FIGURE

esoGPCR Genes Class A Class A Class A Class A Class B

group W6 GPR4s

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21 M R A CR2 2 CCR3. ccR4 CCRs CCRs c CR cas MC1R 3 M GPR2 car 32 kJ CCRL ccR2 ceep2 KBR1

room it is

dros H. D : anni TGig 24 h. '. 242 GPR1 72 H. 243 hit - ENRA 24 HA Ere 24S hu Erin a 2: 24s H.W. cars 247 hit 'Pas 24 HN 408 GPR12 249 wer 250 is H.M. GPRs 251 HM 7 K.M. tars a2 is wer as h pgrass H tire 25 3PR31, 25S H.A. PR as HM “cres as Ku : Patent Application Publication Jun. 22, 2006 Sheet 2 of 9 US 2006/0134109 A1

FIGURE 2

Eamily Class A (Cont) Tachykinin Orphan A9 Orexin Neuropeptide FF Neuropeptide Y Prokineticin2 CCK Orphan As Bombesin EndothelinOrphan A4 Angiotensin Hormone Bradykinin LGR orphan A2 Relaxin/NSL3 Wasopressin 8 Soratostain s opioidinociceptin SREB orphan Neuropeptide W Opsin orphan A8 FMLP O Malatonin Orphan A8 Anaphylatoxin Orphan A3 Leukotriene Galanin Sphingolipid 3 O McH Orphan A1 Cannabinoid Melanocortin ADPfluop-glucose

PAF Prostanoid cysLT o Orphan A7 Orphan A11

Adrenoceptor a Orphan A10 dopamine Adrenocaptor A Purinoceptor

Serotonin SPCLPC Dopamine as Adrieoneculin Sorolonin Proteinase activate Trace armine Eicosanoid Orphan A5 Adenosire Acetylcholine 2. Histamino orphan A2 Motilin, GIrwin Neuroterishn Neuromedinu Orphan A12

Family EMR Latrophilin glutarnate Proto-cadherin BA orphan 83 s' GAA Orphan 32 O Orphan B1 Class F/S

Calcitonin Patent Application Publication Jun. 22, 2006 Sheet 3 of 9 US 2006/0134109 A1

FIGURE 3.

i

Patent Application Publication Jun. 22, 2006 Sheet 5 of 9 US 2006/0134109 A1

FIGURE 5.

Patent Application Publication Jun. 22, 2006 Sheet 6 of 9 US 2006/0134109 A1

FIGURE 6A.

FIGURE 6B. Patent Application Publication Jun. 22, 2006 Sheet 7 of 9 US 2006/0134109 A1

FIGURE 7A. FIGURE 7B.

GPR85. SIH: TT GPR85 - Baseline Temperature

1. a G s E. ww. 3 o w d c C E G C d U > L O chd g o c O o Patent Application Publication Jun. 22, 2006 Sheet 8 of 9 US 2006/0134109 A1

FIGURE 8, PGR854 Conditioned Fear - Context

Genotype Patent Application Publication Jun. 22, 2006 Sheet 9 of 9 US 2006/0134109 A1

FIGURE 9A. FIGURE 9B.

GPR85-Ethanol Sensitivity GPR85 - Ethanol Tolerance

A. VA

V WW P

4. t

V th U al (

Treatment day Genotype US 2006/0134109 A1 Jun. 22, 2006

G PROTEIN COUPLED RECEPTORS AND USES include: (a) polypeptides including a polypeptide sequence THEREOF having at least 90%. 95%, 97%, 98%, or 99% identity to a polypeptide listed in Table 2; (b) polypeptides that include REFERENCE TO TABLE SUBMITTED ON a polypeptide listed in Table 2; (c) polypeptides having at COMPACT DISC least 90%, 95%, 97%, 98%, or 99% sequence identity to a 0001 Pursuant to PCT Administrative Instruction S polypeptide listed in Table 2; and (d) polypeptides listed in 801(a), Table 35 is submitted herewith in triplicate on Table 2. compact disc as “50001.007WO3 Table 35.txt,” created on 0008 Polypeptides of the present invention also include Sep. 8, 2003 and having a size of 1,804 kB, hereby incor variants of the aforementioned polypeptides, including all porated by reference. allelic forms and splice variants. Such polypeptides vary from the reference polypeptide by insertions, deletions, and BACKGROUND OF THE INVENTION Substitutions that may be conservative or non-conservative, 0002 The invention relates to the fields of medicine and or any combination thereof. Particularly desirable variants drug discovery. are those in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 0003 Mammalian G protein coupled receptors (GPCRs) to 2, or from 2 to I amino acids are inserted, Substituted, or constitute a Superfamily of diverse proteins with thousands deleted, in any combination. of members. GPCRs act as receptors for a multitude of different signals. Chemosensory GPCRs (csGPCR) are 0009 Polypeptides of the present invention also include receptors for sensory signals of external origin that are polypeptides that include an amino acid sequence having at sensed as odors, pheromones, or tastes. Most other GPCRs least 30, 50, or 100 contiguous amino acids from any of the respond to endogenous signals, such as peptides, lipids, polypeptides listed in Table 2. Polypeptides of the invention neurotransmitters, or nucleotides. GPCRs falling in the latter are desirably biologically active or are antigenic or immu group are involved in numerous physiological processes, nogenic in an animal, especially in a human. including the regulation of neuronal excitability, metabo 0010. The polypeptides of the present invention may be lism, reproduction, development, hormonal homeostasis, in the form of the “mature' polypeptide, or may be a part of and behavior, and are differentially expressed in many cell a larger polypeptide such as a precursor or a fusion protein. types in the body. It is often advantageous to include an additional amino acid 0004) Of all currently marketed drugs, greater than 30% Sequence that contains Secretory or leader Sequences, pro are modulators of specific GPCRs. Only 10% of GPCRs sequences, sequences that aid in purification, for instance (excluding csGPCRs) are targeted by these drugs, empha multiple histidine residues, or an additional sequence for sizing the potential of the remaining 90% of the gene family stability during recombinant production. for the treatment of human disease. 0011 Polypeptides of the present invention can be pre 0005. Despite the importance of GPCRs in physiology pared in any suitable manner, for instance by isolation from and disease, the size of the GPCR superfamily is still naturally occurring sources, from genetically engineered uncertain. Analyses of genome sequences have generated host cells comprising expression systems, or by chemical markedly varied estimates (Venter, J. C. et al., Science 291, synthesis, using for instance automated peptide synthesizers, 1304-51 (2001); Lander, E. S. et al., Nature 409, 860-921 or a combination of Such methods. For example, polypep (2001); Takeda, S. et al., FEBS Lett 520, 97-101 (2002)). In tides of the invention may be produced by expressing in a addition, while most GPCRs are known to be selectively cell (e.g., a yeast, bacterial, mammalian, or insect cell) a expressed in Subsets of cells, the expression patterns of most vector containing a polynucleotide that encodes a GPCR of GPCRs are incomplete or unknown. Thus, there is a need for the invention under condition in which the polypeptide (e.g., GPCR polypeptides, polynucleotides, antibodies, genetic one listed in Table 2) is expressed. Means for preparing Such models, and modulating compounds for use in the treatment polypeptides are well understood in the art. and diagnosis of a wide variety of disorders and diseases. 0012. In another aspect, the invention features substan tially pure GPCR polynucleotides. Such polynucleotides SUMMARY OF THE INVENTION include: (a) polynucleotides that include a polynucleotide sequence having at least 90%. 95%, 97%, 98%, or 99% 0006 The present invention provides GPCR polypep sequence identity to a polynucleotide listed in Table 2; (b) tides and polynucleotides, recombinant materials, and trans polynucleotides that include a polynucleotide sequence hav genic mice, as well as methods for their production. The ing at least 90%, 95%, 97%, 98%, or 99% sequence identity polypeptides and polynucleotides are useful, for example, in to the reverse complement of polynucleotide listed in Table methods of diagnosis and treatment of diseases and disor 2; (c) polynucleotides that include a polynucleotide listed in ders. The invention also provides methods for identifying Table 2; (d) polynucleotides that are the reverse complement compounds (e.g., agonists or antagonists) using the GPCR of polynucleotide listed in Table 2: (e) polynucleotides polypeptides and polynucleotides of the invention, and for having at least 90%, 95%, 97%, 98%, or 99% sequence treating conditions associated with GPCR dysfunction with identity to a polynucleotide listed in Table 2: (f) polynucle the GPCR polypeptides, polynucleotides, or identified com otides having at least 90%. 95%, 97%, 98%, or 99% pounds. The invention also provides diagnostic assays for sequence identity to the reverse complement of polynucle detecting diseases or disorders associated with inappropriate otide listed in Table 2: (g) polynucleotides listed in Table 2: GPCR activity or levels. (h) reverse complement of polynucleotides listed in Table 2: 0007. In one aspect, the invention features a variety of (i) polynucleotides that include a polynucleotide sequence substantially pure GPCR polypeptides. Such polypeptides encoding a polypeptide sequence having at least 90%. 95%, US 2006/0134109 A1 Jun. 22, 2006

97%, 98%, or 99% identity to a polypeptide listed in Table compound that may be useful for the treatment of a neuro 2: (i) polynucleotides including a nucleotide sequence logical disease or disorder. This method includes the steps of encoding a polypeptide listed in Table 2; and (k) polynucle (a) providing a transgenic non-human mammal (e.g., a otides encoding a polypeptide listed in Table 2. Preferred mouse) overexpressing a nucleic acid molecule encoding a GPCR polynucleotides of the present invention have at least GPCR polypeptide substantially identical to a polypeptide 15, 30, 50 or 100 contiguous nucleotides from any of the listed in any one of Tables 3-14 and 33; (b) contacting the polynucleotides listed in Table 2. transgenic non-human mammal with the candidate com pound; and (c) measuring biological activity of the GPCR 0013 In one embodiment, the polynucleotide is operably polypeptide in the transgenic non-human mammal, wherein linked to a promoter for expression of the polypeptide altered biological activity, relative to that of the GPCR encoded by the polynucleotide. In certain embodiments, the polypeptide in the transgenic non-human mammal not con promoter is a constitutive promoter, is inducible by one or tacted with the compound, indicates that the candidate more external agents, or is cell-type specific. compound may be useful for the treatment of a neurological 0014. In another aspect, the invention features a vector disease or disorder. that includes a GPCR polynucleotide of the invention, the 0020. In still another aspect, the invention features vector being capable of directing expression of the polypep another method for determining whether a candidate com tide encoded by the polynucleotide in a vector-containing pound may be useful for the treatment of a neurological cell. disease or disorder. This method includes (a) providing a 0015. In another aspect, the invention features a method nucleic acid molecule comprising a promoter from a gene of preventing or treating a neurological disease or disorder, encoding a GPCR polypeptide listed in any one of Tables including introducing into a human an expression vector that 3-14 and 33, the promoter operably linked to a reporter includes a nucleic acid molecule encoding a GPCR polypep system; (b) contacting the nucleic acid molecule with the tide Substantially identical to a polypeptide listed in any one candidate compound; and (c) measuring reporter activity, of Tables 3-14 and 33, operably linked to a promoter. wherein altered reporter activity, relative to a nucleic acid 0016. In still another aspect, the invention features a molecule not contacted with the compound, indicates that method of treating or preventing a neurological disease or the candidate compound may be useful for the treatment of disorder, including administering to an animal (e.g., a a neurological disease or disorder. human) a compound that modulates the biological activity of 0021. In another aspect, the invention features yet a GPCR polypeptide substantially identical to a polypeptide another method for determining whether a candidate com listed in any one of Tables 3-14 and 33. pound may be useful for the treatment of a neurological 0017. In yet another aspect, the invention features a disease or disorder. This method includes the steps of: (a) method for determining whether a candidate compound is a providing a GPCR polypeptide substantially identical to a compound that may be useful for the treatment of a neuro polypeptide listed in any one of Tables 3-14 and 33; (b) logical disease or disorder. This method includes the steps of contacting the polypeptide with the candidate compound; (a) providing a GPCR polypeptide substantially identical to and (c) measuring interaction between the candidate com a polypeptide listed in any one of Tables 3-14 and 33; (b) pound and the polypeptide. Interaction between the com contacting the GPCR polypeptide with the candidate com pound and the polypeptide indicates that the candidate pound; and (c) measuring biological activity of the GPCR compound may be useful for the treatment of a neurological polypeptide, wherein altered biological activity, relative to disease or disorder. that of the GPCR polypeptide not contacted with the com 0022. In still another aspect, the invention features pound, indicates that the candidate compound may be useful another method for determining whether a candidate com for the treatment of a neurological disease or disorder. The pound may be useful for the treatment of a neurological GPCR polypeptide can be in a cell or may be in a cell-free disease or disorder. This method includes (a) providing a assay system. GPCR polypeptide substantially identical to a polypeptide 0018. In yet another aspect, the invention features listed in any one of Tables 3-14 and 33; (b) contacting the another method for determining whether a candidate com polypeptide with the candidate compound; and (c) measur pound is a compound that may be useful for the treatment of ing the half-life of the polypeptide, wherein a change in the a neurological disease or disorder. This method includes the half-life of the polypeptide, relative to that of the polypep steps of (a) providing a transgenic non-human mammal tide not contacted with the compound, indicates that the (e.g., a knock-out mouse) having a disruption in a nucleic candidate compound may be useful for the treatment of a acid molecule encoding a GPCR polypeptide substantially neurological disease or disorder. Preferably, the GPCR identical to a polypeptide listed in any one of Tables 3-14 polypeptide is in a cell or a cell free assay system. and 33; (b) contacting the transgenic non-human mammal 0023. In another aspect, the invention features a method with the candidate compound; and (c) measuring biological for determining whether a patient has an increased risk for activity of the GPCR polypeptide in the transgenic non developing a neurological disease or disorder. The method human mammal, wherein altered biological activity, relative includes the step of determining whether the patient has a to that of the transgenic non-human mammal not contacted mutation in a gene encoding a polypeptide listed in one of with the compound, indicates that the candidate compound Tables 3-14 and 33, wherein presence of the mutation may be useful for the treatment of a neurological disease or indicates that the patient has an increased risk for developing disorder. a neurological disease or disorder. 0019. In yet another aspect, the invention features a 0024. In a related aspect, the invention features another method for determining whether a candidate compound is a method for determining whether a patient has an increased US 2006/0134109 A1 Jun. 22, 2006 risk for developing a neurological disease or disorder. This alexia, alexia with agrphia, alexia without agraphia, alien method includes the step of determining whether the patient hand syndrome, Alper's disease, altered sexuality Syn has a polymorphism in a gene encoding a polypeptide listed dromes, alternating hemiplagia, Alzheimer's disease, Alzhe in any one of Tables 3-14 and 33, wherein presence of the imer-like senile dementia, Alzheimer-like juvenile demen polymorphism indicates that the patient has an increased risk tia, amenorrea, aminoacidurias, amnesia, amnesia for for developing a neurological disease or disorder. offences, amok-type reactions, amorphognosia, amphet 0025. In either of these two methods, the mutation or amine addiction, amphetamine or amphetamine-like related polymorphism is preferably associated with an alteration disorders, amphetamine withdrawal, amyloid neuropathy, (for example, a decrease) in the expression level or biologi amyotrophic lateral Sclerosis, anencephaly, aneurysms, cal activity of the polypeptide. angioblastic meningiomas, Angleman's syndrome, anhidro sis, anisocoria, anomia, anomic aphasia, anorexia nervosa, 0026. In another aspect, the invention features another anoSmia, anosognosia, anterior cingulate syndrome, antero method for determining whether a patient has an increased grade amnesia, antibiotic-induced neuromuscular blockade, risk for developing a neurological disease or disorder. The antisocial personality disorder, Anton’s syndrome, anxiety method includes measuring biological activity of a GPCR and obsessive-compulsive disorder syndromes, anxiety dis polypeptide from the patient that is substantially identical to orders, apathy syndromes, aphasia, aphemia, aplasia, apnea, a polypeptide listed in any one of Tables 3-14 and 33, apraxia, arachnoid cyst, archicerebellar syndrome, Arnold wherein increased or decreased levels in the GPCR biologi Chiari malformation, arousal disorders, arrhinencephaly, cal activity, relative to normal levels, indicates that the arsenic poisoning, arteriosclerotic Parkinsonism, arterio patient has an increased risk for developing a neurological venous aneurysm, arteriovenous malformations, aseptic disease or disorder. meningeal reaction, Asperger's syndrome, astereognosis, 0027. In still another aspect, the invention features yet asthenia, astrocytomas, asymbolia, asynergia, ataque de another method for determining whether a patient has an nervios, ataxia, ataxia telangiectasia, ataxic cerebral palsy, increased risk for developing a neurological disease or ataxic dysarthria, athetosis, atonia, atonic seizures, attention disorder. The method includes the step of measuring the deficit disorder, attention-deficit and disruptive behavior patient’s expression level of a polypeptide listed in any one disorders, attention-deficit hyperkinetic disorders, atypical of Tables 3-14 and 33, wherein an alteration in the expres Alzheimer's disease, atypical autism, autism, autism spec Sion, relative to normal, indicates that the patient has an trum disorder, avoidant personality disorder, axial demen increased risk for developing a neurological disease or tias, bacterial endocarditis, bacterial infections, Balint's disorder. Preferably, the expression levels are determined by syndrome, ballism, balo disease, basophilic adenoma, Bas measuring levels of polypeptide or mRNA. sen-Knock outrinzweig syndrome, Batten disease, battered woman syndrome, Behcet syndrome, Bell palsy, benign 0028 Preferred neurological diseases or disorders that essential tremor, benign focal epilepsies of childhood, can be treated or diagnosed using the methods of the benign intracranial hypertension, benxodiazepine depen invention or for which candidate therapeutic compounds dence, bilateral cortical dysfunction, Binswanger's disease, may be identified include, without limitation, abetalipopro bipolar disorder, bipolar type I disorder, bipolar type 2 teinemia, abnormal Social behaviors, absence (petit mal) disorder, blepharospasm, body dysmorphic disorder, epilepsy, absence seizures, abulia, acalculia, acidophilic Bogaert-Bertrand disease, Bogarad syndrome, borderline adenoma, acoustic neuroma, acquired aphasia, acquired personality disorder, botulism, Bouffée Délirante-type reac aphasia with epilepsy (Landau-Kleffner syndrome) specific tions, brachial neuropathy, bradycardia, bradykinesia, brain reading disorder, acquired epileptic aphasia, acromegalic abscess, brain edema, brain fag, brain stem glioma, brain neuropathy, acromegaly, action myoclonus-renal insuffi stem encephalitis, brief psychotic disorder, broca's aphasia, ciency syndrome, acute autonomic neuropathy, acute cer brucellosis, bulimia, bulimia nervosa, butterfly glioma, ebellar ataxia in children, acute depression, acute dissemi cachexia, caffeine related disorders, california encephalitis, nated encephalomyelitis, acute idiopathic sensory callosal agenesis, Canavan's syndrome, cancer pain, can neuronopathy, acute internittent porphyria, acute mania, nabis dependence, cannabis flashbacks, cannabis psychosis, acute mixed episode, acute pandysautonomia, acute poly cannabis related disorders, carcinoma-associated retinopa morphic disorder with symptoms of Schizophrenia, acute thy, cardiac arrest, cavernous malformations, cellular (cyto polymorphic psychotic disorder without symptoms of toxic) edema, central facial paresis, central herniation syn Schizophrenia, acute purulent meningitis, addiction, Addi drome, central neurogenic hyperventilation, central pontine son syndrome, adenovirus serotypes, adjustment disorders, myelinolysis, central post-stroke syndrome (thalamic pain adrenal hyperfunction, adrenal hypofunction, adrenoleu syndrome), cerebellar hemorrhage, cerebellar tonsillar her knock outdystrophy, adrenomyeloneuropathy, advanced niation syndrome, cerebral amyloid (congophilic) angiopa sleep-phase syndrome, affective disorder syndromes, agen thy, cerebral hemorrhage, cerebral malaria, cerebral palsy, esis of the corpus callosum, agnosia, agoraphobia, agraphia, cerebral Subdural empyema, cerebrotendinous Xanthomato agyria, agyria-pachygyria, ahylognosia, Aicardi syndrome, sis, cerebrovascular disorders, cervical tumors, cestodes, AIDS, akathisia, akinesia, akinetic mutism, akinetopsia, Charcot-Carie-tooth disease, Chediak-Cigashi disease, alcohol abuse, alcohol dependence syndrome, alcohol neu Cheiro-oral syndrome, chiari malformation with hydroceph ropathy, alcohol related disorders, alcoholic amblyopia, alus, childhood disintegrative disorder, childhood feeding alcoholic blacknock oututs, alcoholic cerebellar degenera problems, childhood sleep problems, cholesteatomas, chor tion, alcoholic dementia, alcoholic hallucinosis, alcoholic domas, chorea, chorea gravidarum, choreoathetosis, chro polyneuropathy, alcohol-induced anxiety disorders, alcohol mophobe adenoma, chromosomal disorders, chronic biplar induced dementia, alcohol-induced mood disorders, alcohol major depression, chronic bipolar disorder, chronic demy induced psychosis, alcoholism, Alexander's syndrome, elinating polyneuritis, chronic depression, chronic fatigue US 2006/0134109 A1 Jun. 22, 2006 syndrome, chronic gm2 gangliosidosis, chronic idiopathic dysthesia, dysthymia, dystonia, dystrophinopathies, early sensory neuropathy, chronic inflammatory demyelinating adolescent gender identity disorder, early infantile epileptic polyneuropathy, chronic inflammatory demyelinating encephalopthy (Ohtahara syndrome, early myoclonic epi polyradiculoneuropathy, chronic pain, chronic paroxysmal leptic encephalopathy, Eaton-Lambert syndrome, echino hemicrania, chronic sclerosing panencephalitis, chronic coccus (hydatid cysts), echolalia, echovirus, eclampsia, traumatic encphalopathy, chronobiological disorders, circa Edwards syndrome, elimination disorders, embolismintrac dian rhythm disorder, circadian rhythm disorders, Claude's erebral hemorrhage, Emery-Dreifuss muscular dystrophy, syndrome, clonic seizures, cluster headache, cocaine addic encephalitis lethargica, encephaloceles, encephalotrigemi tion, cocaine withdrawal, cocaine-related disorders, Cock nal angiomatosis, enophthalmos, enterovirus, enuresis, eosi ayne's syndrome, colloid cysts of the third ventricle, colo nophilic meningitis, ependymoma, epidural spinal cord rado tick fever, coma, communicating hydrocephalus, compression, epilepsy, episodic ataxia, epstein-barr, equine communication disorders, complex partial seizures, com encephalomyelitis, erectile dysfunction, essential thromb pression neuropathy, compulsive buying disorder, concep ocythemia, essential tremor, esthesioneuroblastoma, exces tual apraxia, conduct disorders, conduction aphasia, conduc sive daytime Somnolence, excessive secretion of antidiuretic tion apraxia, congenital analgesia, congenital hormone, excessive sleepiness, exhibitionism, expressive cytomegalovirus disease, congenital hydrocephalus, con language disorder, extramedullary tumors, extrasylvian genital hypothyroidism, congenital muscular dystrophy, aphasias, extratemporal neocortical epilepsy, fabry's dis congenital myasthenia, congenital myotonic dystrophy, con ease, facioscapulohumeral muscular dystrophy, factitious genital rubella syndrome, congophilic angiopathy, constipa disorder, factitious disorders, false memories, familial dys tion, coprophilia, cornedlia de lange syndrome, cortical autonomia, familial periodic paralysis, familial spastic para dementias, cortical heteropias, corticobasal degeneration, paresis, familial spastic paraplegias, fear disorders, feeding corticobasal ganglionic degeneration, coxsackievirus, cra and eating disorders of infancy or early childhood, female nial meningoceles, craniopharyngioma, craniorachischisis, sexual arousal disorder, fetal alcohol syndrome, fetishism, craniosynostosis, cranium bifidum, cretinism, Creutzfeldt flaccid dysarthria, floppy infant syndrome, focal inflamma Jaknock outb disease, Cri-du-Chat syndrome, cruciate tory demyelinating lesions with mass effect, focal neonatal hemiplegia, cryptococcal granulomas, cryptococcosis, cul hypotonia, folie a deux, foramen magnum tumors, Foville's turally related syndromes, culturally Stereotyped reactions to syndrome, fragile-X syndrome, Freidrich s ataxia, Frolich extreme environmental conditions (arctic hysteria), Cushing syndrome, frontal alexia, frontal convexity syndrome, fron syndrome, cyclothymia, cysticercosis, cytomegalovirus, totemporal dementia, frontotemporal dementias, frotteur Dandy-Walker malformation, deafness, defects in the ism, fungal infection, galactocerebroside lipidosis, galactor metabolism of amino acids, dehydration, Deerine-Roussy rhea, ganglioneuroma, Gaucher disease, gaZe palsy, gender syndrome, Deerine-Sottas disease, delayed and advanced identity disorder, generalized anxiety disorder, genital sleep phase syndromes, delayed ejaculation, delayed shrinking syndrome (Knock outro, Suo-Yang), germ cell puberty, delayed-sleep-phase syndrome, delerium due to tumors, Gerstmann's syndrome, Gerstmann-Strauissler Syn alcohol, delerium due to intoxication, delerium due to with drome, Gerstmann-Straussler-Schenker disease, Gertmann's drawal, delirium, dementia, and amnestic and other cogni syndrome, gestational Substance abuse syndromes, giant tive disorders, delusional disorder, delusional disorder: ero axonal neuropathy, gigantism, Gilles de la Tourette Syn tomania Subtype, delusional disorder: grandiose Subtype, drome, glioblastoma multiforme, gliomas, gliomatosis cere delusional disorderjealousy Subtype, delusional misidenti bri, global aphasia, glossopharyngeal neuralgia, glycogen fication syndromes, dementia due to HIV disease, dementia storage diseases, gm1-gangliosidosis, gm2-gangliosidoses, pugilistica, dementias, dementias associated with extrapy granular cell tumor, granulocytic brain edema, granulomas, ramidal syndrome, dentatorubral-pallidoluysian atrophy, granulomatous angiitis of the brain, Grave's disease, grow dependent personality disorder, depersonalization disorder, ild typeh hormone deficit, growild typeh-hormone secreting depression, depressive personality disorder, dermoids, adenomas, guam-Parkinson complex dementia, Guillain developmental speech and language disorder, devic Syn Barré syndrome, Hallervorden-Spatz disease, hallucinogen drome, devivo disease, diabetes, diabetes insipidus, diabetic persisting perception disorder, hallucinogen related disor neuropathy, dialysis demential, dialysis dysequilibrium syn ders, hartinup disease, headache, helminthic infections (tri drome, diencephalic dementias, diencephalic dysfunction, chinellosis), hemangioblastomas, hemangiopericytomas, diencephalic syndrome of infancy, diencephalic vascular hemiachromatopsia, heimianesthesia, hemianopsia, dementia, diffuse Sclerosis, digestive disorders, diphtheria, hemibalism, hemibalismus, hemihypacusis, hemihypesthe diplopia, disarthria, disassociation apraxia, disorders of car sia, hemiparesis, hemispatial neglect, hemophilus influenza bohydrate metabolism, disorders of excessive Somnolence, meningitis, hemorrhagic cerebrovascular disease, hepatic disorders of metal metabolism, disorders of purine metabo coma, hepatic encephalopathy, hepatolenticular degenera lism, disorders of sexual arousal, disorders of sexual aver tion (Wilson disease), hereditary amyloid neuropathy, Sion, disorders of sexual desire, disorders of the sleep-wake hereditary ataxias, hereditary cerebellar ataxia, hereditary schedule, dissociative disorders, dorsolateral tegmental pon neuropathies, hereditary nonprogressive chorea, hereditary tine syndrome, Down syndrome, Down syndrome with predisposition to pressure palsies, hereditary sensory auto dementia, drug dependance, drug overdose, drug-induced nomic neuropathy, hereditary sensory neuropathy, heredi myasthenia, Duchenne muscular dystrophy, dwarfism, dys tary spastic paraplegia, hereditary tyrosinemia, hermichorea, arthria, dysdiadochokinesia, dysembryoplastic neuroepithe hermifacial spasm, herniation syndromes, herpes encepha lial tumor, dysexecutive syndrome, dysgraphia, dyskinesia, litis, herpes infections, herpes Zoster, herpres simplex, het dyskinetic cerebral palsy, dyslexia, dysmetria, dysomnia, erotopia, hexacarbon neuropathy, histrionic personality dis dysosmia, dyspareunia, dysphagia, dysphasia, dysphonia, order, HIV. Holmes-Adie syndrome, homonymous dysplasia, dyspnea, dysprosody, dyssomnia, dyssynergia, quadrantaposia, Homer's syndrome, human f3-mannosido US 2006/0134109 A1 Jun. 22, 2006 sis, Hunter's syndrome, Huntington's chorea, Huntington's without melancholia, major depressive (unipolar) disorder, disease, Hurler's syndrome, Hwa-Byung, hydraencephaly, male orgasmic disorder, malformations of septum pelluci hydrocephalus, hyper thyroidism, hyperacusis, hyperalge dum, malignant peripheral nerve sheath tumors, malingers, sia, hyperammonemia, hypereosinophilic syndrome, hyper mania, mania with psychotic features, mania without psy glycemia, hyperkalemic periodic paralysis, hyperkinesia, chotic features, maple syrup urine disease, Marchiafava hyperkinesis, hyperkinetic dysarthria, hyperosmia, hyperos Bignami syndrome, Marcus Gunn syndrome, Marie-Foix molar hyperglygemic nonketonic diabetic coma, hyperpar syndrome, Marinesco-Sjögren syndrome, Maroteaux-Lamy athyroidism, hyperphagia, hyperpituitarism, hyperpro syndrome, masochism, masturbatory pain, measles, medial lactinemia, hypersexuality, hypersomnia, hypersomnia frontal syndrome, medial medullary syndrome, medial teg secondary to drug intake, hypersomnia-Sleep-apnea Syn mental syndrome, medication-induced movement disorders, drome, hypersomnolence, hypertension, hypertensive medullary dysfunction, medulloblastomas, medulloepithe encephalopathy, hyperthermia, hyperthyroidism (Graves lioma, megalencephaly, melanocytic neoplasms, memory disease), hypertonia, hypnagogic (predormital) hallucina disorders, memory disturbances, meniere syndrome, tions, hypnogenic paroxysmal dystonia, hypoadrenalism, meningeal carcinomatosis, meningeal sarcoma, meningial hypoalgesia, hypochondriasis, hypoglycemia, hypoinsulin gliomatosis, meningiomas, meningism, meningitis, menin ism, hypokalemic periodic paralysis, hypokinesia, hypoki gococcal meningitis, mental neuropathy (the numb chin netic dysarthria, hypomania, hypoparathyroidism, hypoph syndrome), mental retardation, mercury poisoning, rmeta agia, hypopituitarism, hypoplasia, hyposmia, hyposthenuria, bolic neuropathies, metachromatic leuknock outdystrophy, hypotension, hypothermia, hypothyroid neuropathy, metastatic neuropathy, metastatic tumors, metazoal infec hypothyroidism, hypotonia, Hyrler syndrome, hysteria, ide tions, microcephaly, microencephaly, micropolygyria, mid ational apraxia, ideomotor apraxia, idiopathic hypersomnia, brain dysfunction, midline syndrome, migraine, mild idiopathic intracranial hypertension, idiopathic orthostatic depression, Millard-Gubler syndrome, Miller-Dieker syn hypotension, immune mediated neuropathies, impersistence, drome, minimal brain dysfunction syndrome, miosis, mito impotence, impulse control disorders, impulse dyscontrol chondrial encephalopathy with lactic acidosis and stroke and aggression syndromes, impulse-control disorders, (melas), mixed disorders of scholastic skills, mixed dysar incontinence, incontinentia pigmenti, infantile encephalopa thrias, mixed transcortical aphasia, Möbius syndrome, Mol thy with cherry-red spots, infantile neuraxonal dystrophy, laret meningitis, monoclonal gammopathy, mononeuritis infantile spasms, infantilism, infarction, infertility, influ nultiplex, monosymptomatic hypochondriacal psychosis, enza, inhalant related disorders, insomnias, insufficient sleep mood disorders, Moritz Benedikt syndrome, Morquio syn syndrome, intention tremor, intermittent explosive disorder, drome, Morton's neuroma, motor neuron disease, motor internuclear ophthalmoplegia, interstitial (hydrocephalic) neurone disease with dementia, motor neuropathy with edema, intoxication, intracranial epidural abscess, intracra multifocal conduction block, motor skills disorder, nial hemorrhage, intracranial hypotension, intracranial mucolipidoses, mucopolysaccharide disorders, muco tumors, intracranial venous-sinus thrombosis, intradural polysaccharidoses, multifocal eosinophilic granuloma, mul hematoma, intramedullary tumors, intravascular lymphoma, tiple endocrine adenomatosis, multiple myeloma, multiple ischemia, ischemic brain edema, ischemic cerebrovascular Sclerosis, multiple system atrophy, multiple systems atrophy, disease, ischemic neuropathies, isolated inflammatory multisystemic degeneration with dementia, mumps, Mun demyelinating CNS syndromes, Jackson-Collet syndrome, chausen syndrome, Munchausen syndrome by proxy, mus Jaknock outb-Creutzfeld disease, Japanese encephalitis, jet cular hypertonia, mutism, myasthenia gravis, mycoplasma lag syndrome, Joseph disease, Joubert's syndrome, juvenile pneumoniae infection, myoclonic seizures, myoclonic-as neuroaxonal dystrophy, Kayak-Svimmel, Keams-Sayre Syn tatic epilepsy (doose syndrome), myoclonus, myotonia con drome, kinky hair disease (Menkes syndrome), Kleine genita, myotonic dystrophy, myotonic muscular dystrophy, Levin Syndrome, kleptomania, Klinefelter's syndrome, Klu nacolepsy, narcissistic personality disorder, narcolepsy, nar ver-Bucy syndrome, Knock outerber-Salus-Elschnig colepsy-cataplexy syndrome, necrophilia, nectrotizing syndrome, Knock outrsaknock outffs syndrome, krabbe encephalomyelopathy, Nelson's syndrome, neocerebellar disease, krabbe leuknock outdystrophy, Kugelberg-We syndrome, neonatal myasthenia, neonatal seizures, nervios, lander syndrome, kuru, Lafora's disease, language deficits, nerves, neurasthenia, neuroacanthocytosis, neuroaxonal language related disorders, latah-type reactions, lateral mass dystrophy, neurocutaneous disorders, neurofibroma, neu herniation syndrome, lateropulsation, lathyrism, Laurence rofibromatosis, neurogenic orthostatic hypotension, neuro Moon Biedl syndrome, Laurence-Moon syndrome, lead leptic malignant syndrome, neurologic complications of poisoning, learning disorders, leber hereditary optic atrophy, renal transplantation, neuromyelitis optica, neuromyotonia left ear extinction, legionella pneumophilia infection, (Isaacs syndrome), neuronal ceroid lipofuscinoses, neuro Leigh's disease, Lennoc-Gastaut syndrome, Lennox-Gas ophthalamic disorders, neuropathic pain, neuropathies asso taut's syndrome, leprosy, leptospirosis, Lesch-Nyhan Syn ciated with infections, neuropathy associated with cryoglo drome, leukemia, leuknock outdystrophies, Levy-Roussy bulins, neuropathy associated with hepatic diseases, syndrome, lewy body dementia, lewy body disease, limb neuropathy induced by cold, neuropathy produced by girdle muscular dystrophies, limbic encephalitis, limbic chemicals, neuropathy produced by metals, neurosyphilis, encephalopathy, lissencephaly, localized hypertrophic neu new variant Creutzfeldt-Jaknock outb disease, nicotine ropathy, locked-in syndrome, logoclonia, low pressure head dependence, nicotine related disorders, nicotine withdrawal, ache, Lowe syndrome, lumbar tumors, lupus anticoagulants, niemann-pick disease, nocturnal dissociative disorders, noc lyme disease, lyme neuropathy, lymphocytic choriomenin turnal enuresis, nocturnal myoclonus, nocturnal sleep-re gitis, lymphomas, lysosomal and other storage diseases, lated eating disorders, noecerbellar syndrome, non-alzher macroglobinemia, major depression with melancholia, imer frontal-lobe degeneration, nonamyloid major depression with psychotic features, major depression polyneuropathies associated with plasma cell dyscrasia, US 2006/0134109 A1 Jun. 22, 2006 non-lethal Suicial behavior, nonlocalizing aphasic Syn frontal lobe Syndrome, premenstrual stress disorder, pre dromes, normal pressure hydrocephalus, Nothnagel's Syn menstrual syndrome, primary amebic meningoencephalitis, drome, nystagmus, obesity, obsessive-compulsive (anankas primary CNS lymphoina, primary idiopathic thrombosis, tic) personality disorder, obsessive-compulsive disorder, primary lateral Sclerosis, primitive neuroectodermal tumors, obstetric factitious disorder, obstructive hyrocephalus, prion disease, problems related to abuse or neglect, progres obstructive sleep apnea, obstructive sleep apnoea syndrome, sive bulbar palsy, progressive frontal lobe dementias, pro obstructive sleep hypopnoea syndrome, occipital dementia, gressive multifocal lueknock outencephalopathy, progres occlusive cerebrovascular disease, oculocerebrorenal Syn sive muscular atrophy, progressive muscular dystrophies, drome of lowe, oculomotor nerve palsy, oculopharyngeal progressive myoclonic epilepsies, progressive myoclonus muscular dystrophy, oligodendrogliomas, olivopontocer epilepsies, progressive non-fluent aphasia, progressive par ebellar atrophy, ondine's curse, one and a half syndrome, tial epilepsies, progressive rubella encephalitis, progressive onychophagia, opiate dependance, opiate overdose, opiate Sclerosing poliodystrophy (Alpers disease), progressive Sub withdrawal, opioid related disorders, oppositional defiant cortical gliosis, progressive Supranuclear palsy, progressive disorder, opSoclonus, orbitofrontal syndrome, orgasmic Supranuclear paralysis, progrssive external ophthalmople anhedonia, orgasmic disorders, osteosclerotic myeloma, gia, prolactinemia , prolactin-sectreting adenomas, other disorders of infancy, childhood, or adolescence, other prosopagnosia, protozoan infection, pseudobulbar palsy, medication-induced movement disorders, pachygyria, pae pseudocyesis, pseudodementia, psychic blindness, psy dophilia, pain, pain syndromes, painful legs-moving toes chogenic excoriation, psychogenic fugue, psychogenic pain syndrome, paleocerebellar syndrome, palilalia, panhypopi syndromes, psychological mutism, psychosis after brain tuitarism, panic disorder, panic disorders, papillomas of the injury, psychotic syndromes, ptosis, public masturbation, choroid plexus, paraganglioma, paragonimiasis, paralysis, puerperal panic, pulmonary edema, pure word deafness, paralysis agitans (shaking palsy), paramyotonia congenita, pyromania, quadrantanopsia, rabies, radiation neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic cer Ramsay Hunt syndrome, rape traume syndrome, rapid ebellar syndrome, paraneoplastic neuropathy, paraneoplastic cycling disorder, rapid ejaculation, Raymond-Cestan syndromes, paranoia, paranoid personality disorder, para Chenais syndrome, receptive language disorder, recovered noid psychosis, paraphasia, paraphilias, paraphrenia, para memories, recurrent bipolar episodes, recurrent brief dpres sitic infections, parasomnia, parasomnia overlab disorder, Sion, recurrent hypersomnia, recurrent major depression, parenchymatous cerebellar degeneration, paresis, paresthe refsum disease, reiterative speech disturbances, relational sia, parinaud's syndrome, Parkinson's disease, Parkinson problems, rem sleep behavior disorder, rem sleep behavioral dementia complex of guam, Parkinsonism, Parkinsonism disorder, repetitive self-mutilation, repressed memories, res plus syndromes, Parkinson's disease, paroxysmal ataxia, piratory dysrhythmia, restless legs syndrome, Rett's Syn paroxysmal dyskinesia, partial (focal) seizures, partialism, drome, Reye syndrome, rhythmic movement disorders, passive-aggressive (negativistic) personality disorder, rocky mountain spotted fever, rostral basal pontine Syn Patau’s syndrome, pathological gambling, peduncular hal drome, rubella, Rubinstein-Taybi syndrome, sadistic person lucinosis, Pelizaeus-Merzbacher disease, perineurioma, ality disorder, sala disease, Sandhoff disease, Sanfilippo peripheral neuropathy, perisylvian syndromes, periventricu syndrome, sarcoid neuropathy, sarcoidosis, Scapuloperoneal lar leuknock outmalacia, periventricular white matter disor syndromes, Schistosomiasis (bilharziasis), Schizencephaly, der, periventricular-intraventricular hemorrhage, pernicious schizoaffective disorder, schizoid personality disorder, anemia, peroneal muscular atrophy, peroxisomal diseases, Schizophrenia, Schizophrenia and other psychotic disorders, perseveration, persistence of cavum septi pellucidi, persis Schizophrenia-like psychosis, Schizophreniform disorder, tent vegetative state, personality disorders, pervasive devel Schizotypal personality disorder, School-refusal anxiety dis opmental disorders, phencyclidine (or phencyclidine-like) order, Schwannoma, Scrub typhus, seasonal depression, sec related disorders, phencyclidine delirium, phencyclidine ondary spinal muscular atrophy, secondary thrombosis, psychosis, phencyclidine-induced psychotic disorder, phe sedative hypnotic or anxiolytic-related disorders, seizure nylketonuria, phobic anxiety disorder, phonic tics, photore disorders, selective mutism, self-defeating (masochistic) cepto degeneration, pibloktoq, Pick's disease, pineal cell personality disorder, semen-loss syndrome (shen-k'uei, tumors, pineoblastoma, pineocytoma, pituitary adenoma, dhat, jiryan, Sukra prameha), senile chorea, senile dementia, pituitary apoplexy, pituitary carcinoma, pituitary dwarfism, sensory perineuritis, separation anxiety disorder, septal Syn placebo effect, Plummer's disease, pneumococcal meningi drome, septo-optic dysplasia, severe hypoxia, severe myo tis, poikilolthermia, polio, polycythemia Vera, polydipsia, clonic epilepsy, sexual and gender identity disorders, sexual polyglucosan storage diseases, polymicrogyria, polymyosi disorders, sexual dysfunctions, sexual pain disorders, sexual tis, polyneuropathy with dietary deficiency states, poly Sub sadism, Shapiro syndrome, shift work sleep disorder, Shy stance related disorder, polyuria, pontine dysfunction, pon Drager syndrome, sialidosis, sialidosis type 1, sibling rivalry to Subicular neuronal necrosis, porencephaly, porphyric disorder, sickle cell anemia, Simmonds disease, simple neuropathy, portal-systemic encephalopathy, postcoital partial seizures, simultanagnosia, sleep disorders, sleep headaches, postconcussion syndrome, postencephalic Par paralysis, sleep terrors, sleep-related enuresis, sleep-related kinson syndrome, posthemorrhagic hydrocephalus, postin gastroesophageal reflux syndrome, sleep-related headaches, flammatory hydrocephalus, postpartum depression, postpar sleep-wake disorders, sleepwalking, Smith-Magenis Syn tum psychoses, postpolio syndrome, postpsychotic drome, Social anxiety disorder, social phobia, Social rela depression, post-stroke hypersomnia, post-traumatic amne tionship syndromes, somatoform disorders, Somnambulism, sia, post-traumatic epilepsy, post-traumatic hypersomnia, Sotos syndrome, spasmodic dysphonia, spasmodic torticol post-traumatic movement disorders, post-traumatic stress lis (wry neck), spastic cerebral palsy, spastic dysarthria, disorder, post-traumatic syndromes, Prader-Willi syndrome, specific developmental disorder of motor function, specific precocious puberty, prefrontal dorsolateral syndrome, pre developmental disorders of scholastic skills, specific devel US 2006/0134109 A1 Jun. 22, 2006 opmental expressive language disorder, specific develop 15 and 33, the promoter operably linked to a reporter mental receptive language disorder, specific disorders of system; (b) contacting the nucleic acid molecule with the arithmetical skills, specific phobia, specific speech articula candidate compound; and (c) measuring reporter activity, tion disorder, specific spelling disorder, speech impairment, wherein altered reporter activity, relative to a nucleic acid spina bifida, spinal epidural abcess, spinal muscular atro molecule not contacted with the compound, indicates that phies, spinocerebellar ataxias, spirochete infections, spongi the candidate compound may be useful for the treatment of form encephalopathies, spongy degeneration of the nervous a disease or disorder of the adrenal gland. system, St. Louis encephalitis, stammer, staphylococcal 0030. In another aspect, the invention features yet meningitis, startle syndromes, status miarmoratus, Steele another method for determining whether a candidate com richardson-olszewski syndrome, stereotypic movement dis pound may be useful for the treatment of a disease or order, Stereotypies, stiff-man syndrome, stiff-person Syn disorder of the adrenal gland. This method includes the steps drome, stimulant psychosis, Strachan syndrome (nutritional of: (a) providing a GPCR polypeptide substantially identical neuropathy), Streptococcal meningitis, striatonigral degen to a polypeptide listed in Tables 15 and 33; (b) contacting the eration, stroke, strongyloidiasis, Sturge-Weber disease polypeptide with the candidate compound; and (c) measur (Krabbe-Weber-Dimitri disease), stutter, subacute combined degeneration of the spinal cord, Subacute motor neuronopa ing interaction of the candidate compound to the polypep thy, Subacute necrotic myelopathy, Subacute Sclerosing tide. Interaction of the compound to the polypeptide indi panencephalitis, Subacute sensory neuronopathy, Subarach cates that the candidate compound may be useful for the niod hemorrhage, Subcortical aphasia, Subfalcine herniation treatment of a disease or disorder of the adrenal gland. syndrome, Substance abuse, Substance related disorders, 0031. In still another aspect, the invention features Sudanophilic leuknock outdystrophis, Sudden infant death another method for determining whether a candidate com syndrome, Suicide, Sulfatide lipidosis, Susto, espanto, meido, pound may be useful for the treatment of a disease or Sydenham chorea, Symetric neuropathy associated with car disorder of the adrenal gland. This method includes (a) cinoma, sympathotonic orthostatic hypotension, Syncope, providing a GPCR polypeptide substantially identical to a syndromes related to a cultural emphasis on learnt dissocia polypeptide listed in Tables 15 and 33; (b) contacting the tion, syndromes related to a cultural emphasis on presenting polypeptide with the candidate compound; and (c) measur a physical apprearance pleasing to others (taijin-kyofu reac ing the half-life of the polypeptide, wherein an alteration in tions), syndromes related to acculturative stress, Syringob the half-life of the polypeptide, relative to that of the ulbia, Syringomyelia, Systemic lupus erythematosus, tachy polypeptide not contacted with the compound, indicates that cardia, tachypnea, Tangier disease, tardive dyskinesia, Tay the candidate compound may be useful for the treatment of Sachs disease, telangiectasia, telencephalic leuknock a disease or disorder of the adrenal gland. Preferably the outencephalopathy, telephone scatologia, temporal lobe epi GPCR polypeptide is in a cell or a cell free assay system. lepsy, temporoparietal dementia, tension-type headache, ter 0032. In another aspect, the invention features a method atomas, tetanus, tetany, thalamic syndrome, thallium poi for determining whether a patient has an increased risk for soning, thoracic tumors, thrombotic thrombocytopenic developing a disease or disorder of the adrenal gland. The purpura, thyroid disorders, tic disorders, tick paralysis, tick method includes the step of determining whether the patient borne encephalitis, tinnitis, tomaculous neuropathy, tonic has a mutation in a gene encoding a polypeptide listed in seizures, tonic-clonic seizures, torticollis, Tourette Syn Tables 15 and 33, wherein presence of the mutation indicates drome, toxic neuropathies, toxoplasmosis, transcortical that the patient has an increased risk for developing a disease motor aphasia, transcortical sensory aphasia, transient epi or disorder of the adrenal gland. leptic amnesia, transient global amnesia, transitional scle rosis, transvestic fetishism, traumatic brain injury, traumatic 0033. In a related aspect, the invention features another neuroma, traumiatic mutism, tremors, trichinosis, trichotil method for determining whether a patient has an increased lomania, trigeminal neuralgia, trochlear nerve palsy, tropical risk for developing a disease or disorder of the adrenal ataxic neuropathy, tropical spastic paraparesis, trypanoso gland. This method includes the step of determining whether miasis, tuberculomas, tuberculous meningitis, tuberous scle the patient has a polymorphism in a gene encoding a rosis, tumors, Turner's syndrome, typhus fever, ulegyria, polypeptide listed in Tables 15 and 33, wherein presence of uncinate fits, Unverricht-Lundborg's disease, upper airway the polymorphism indicates that the patient may have an resistance syndrome, upward transtentorial herniation syn increased risk for developing a disease or disorder of the drome, uremic encephalopathy, uremic neuropathy, uro adrenal gland. philia, vaccinia, Varicella-Zoster, Vascular dementia, Vascu 0034. In either of these two methods, the mutation or lar malformations, vasculitic neuropathies, Vasogenic polymorphism is preferably associated with an alteration edema, Velocardiofacial syndrome, venous malformations, (for example, a decrease) in the biological activity of the ventilatory arrest, vertigo, Vincristine mammal, wherein polypeptide. altered biological; activity, relative to that of the transgenic 0035) In another aspect, the invention features another non-human mammal not contacted with the compound, method for determining whether a patient has an increased indicates that the candidate compound may be useful for the risk for developing a disease or disorder of the adrenal treatment of a disease or disorder of the adrenal gland. gland. The method includes measuring biological activity of 0029. In still another aspect, the invention features a GPCR polypeptide from the patient that is substantially another method for determining whether a candidate com identical to a polypeptide listed in Tables 15 and 33, wherein pound may be useful for the treatment of a disease or increased or decreased levels in the GPCR biological activ disorder of the adrenal gland. This method includes (a) ity, relative to normal levels, indicates that the patient has an providing a nucleic acid molecule comprising a promoter increased risk for developing a disease or disorder of the from a gene encoding a GPCR polypeptide listed in Tables adrenal gland. US 2006/0134109 A1 Jun. 22, 2006

0036). In still another aspect, the invention features yet includes a nucleic acid molecule encoding a GPCR polypep another method for determining whether a patient has an tide substantially identical to a polypeptide listed in Table increased risk for developing a disease or disorder of the 15. adrenal gland. The method includes the step of measuring 0039. In yet another aspect, the invention features a the patient’s expression levels of a polypeptide listed in non-human mammal (e.g., a mouse), having a mutation in a Tables 15 and 33, wherein altered levels in the expression, nucleic acid molecule encoding a GPCR polypeptide sub relative to normal, indicate that the patient has an increased stantially identical to a polypeptide listed in Table 15. risk for developing a disease or disorder of the adrenal gland. Preferably, the expression levels are determined by 0040. In a related aspect, the invention features a cell measuring levels of polypeptide or mRNA. from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a GPCR polypeptide 0037 Diseases of the adrenal gland that can be treated or substantially identical to a polypeptide listed in Table 15. diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 0041. In another aspect, the invention features a cell from 11 -hydroxylase deficiency, 17-hydroxylase deficiency, a non-human mammal having a mutation in a nucleic acid 33-dehydrogenase deficiency, acquired immune deficiency molecule encoding a GPCR polypeptide substantially iden syndrome, ACTH-dependent adrenal hyperfunction (Cush tical to a polypeptide listed in Table 15. ing disease), ACTH-independent adrenal hyperfunction, 0042. In another aspect, the invention features a method acute adrenal insufficiency, adrenal abscess, adrenal of preventing or treating a disease of the colon including adenoma, adrenal calcification, adrenal cysts, adrenal introducing into a human an expression vector that includes cytomegaly, adrenal dysfunction in glycerol kinase defi a nucleic acid molecule encoding a GPCR polypeptide ciency, adrenal hematoma, adrenal hemorrhage, adrenal substantially identical to a polypeptide listed in Tables 16 histoplasmosis, adrenal hyperfunction, adrenal hyperplasia, and 33, operably linked to a promoter. adrenal medullary hyperplasia, adrenal myelolipoma, adre nal tuberculosis, adrenocortical adenoma, adrenocortical 0043. In still another aspect, the invention features a adenoma with primary hyperaldosteronism (Conn's Syn method of treating or preventing a disease of the colon drome), adrenocortical carcinoma, adrenocortical carcinoma including administering to an animal (e.g., a human) a with Cushing's syndrome, adrenocortical hyperfunction, compound that modulates the biological activity of a GPCR adrenocortical insufficiency, adrenocortical neoplasms, polypeptide Substantially identical to a polypeptide listed in adrenoleuknock outdystrophy, amyloidosis, anencephaly, Tables 16 and 33. autoimmune Addison's disease, Beckwith-Wiedemann syn 0044) In yet another aspect, the invention features a drome, bilateral adrenal hyperplasia, chronic insufficiency method for determining whether a candidate compound is a of adrenocortical hormone synthesis, complete 21-hydroxy compound that may be useful for the treatment of a disease lase deficiency, congenital adrenal hyperplasia, congenital or disorder of the colon. This method includes the steps of adrenal hypoplasia, cortical hyperplasia, desmolase defi (a) providing a GPCR polypeptide substantially identical to ciency, ectopic ACTH syndrome, excess aldosterone secre a polypeptide listed in Tables 16 and 33; (b) contacting the tion, excess cortisol Secretion (Cushing's syndrome), excess GPCR polypeptide with the candidate compound; and (c) secretion of adrenocortical hormones, excess sex hormone measuring biological activity of the GPCR polypeptide, secretion, familial glucocorticoid deficiency, functional wherein altered biological activity, relative to that of the “black' adenomas, ganglioneuroblastoma, ganglioneuroma, GPCR polypeptide not contacted with the compound, indi glucocorticoid remediable hyperaldosteronism, herpetic cates that the candidate compound may be useful for the adrenalitis, hyperaldosteronism, idiopathic Addison's dis treatment of a disease or disorder of the colon. The GPCR ease, idiopathic hyperaldosteronism with bilateral hyperpla polypeptide can be in a cell or in a cell-free assay system. sia of Zona glomerulosa, latrogenic hypercortisolism, lyso Somal storage diseases, macronodular hyperplasia, 0045. In yet another aspect, the invention features a macronodular hyperplasia with marked adrenal enlarge method for determining whether a candidate compound is a ment, malignant lymphoma, malignant melanoma, meta compound that may be useful for the treatment of a disease static carcinoma, metastatic tumors, micronocular hyperpla or disorder of the colon. This method includes the steps of sia, multiple endocrine neoplasia syndromes, multiple (a) providing a transgenic non-human mammal (e.g., a endocrine neoplasia type 1 (Wermer syndrome), multiple knock-out mouse) having a disruption in a nucleic acid endocrine neoplasia type 2a (Sipple syndrome), multiple molecule encoding a GPCR polypeptide substantially iden endocrine neoplasia type 2b, neuroblastoma, Niemann-Pick tical to a polypeptide listed in Tables 16 and 33; (b) disease, ovarian thecal metaplasia, paraganglioma, partial contacting the transgenic non-human mammal with the 21-hydroxylase deficiency, pheochromocytoma, primary candidate compound; aldosteronism (Conn's syndrome), primary chronic adrenal 0046) and (c) measuring biological activity of the GPCR insufficiency (Addison's disease), primary hyperaldoster polypeptide in the transgenic non-human mammal, wherein onism, primary mesenchymal tumors, primary pigmented altered biological activity, relative to that of the transgenic nodular adrenocortical disease, salt-wasting congenital adre non-human mammal not contacted with the compound, nal hyperplasia, secondary Addison's disease, secondary indicates that the candidate compound may be useful for the hyperaldosteronsim, selective hypoaldosteronism, simple treatment of a disease or disorder of the colon. Virilizing congenital adrenal hyperplasia, Waterhouse-Frid erichsen syndrome, and Wolman's disease. 0047. In yet another aspect, the invention features a method for determining whether a candidate compound is a 0038. In another aspect, the invention features a non compound that may be useful for the treatment of a disease human mammal (e.g., a mouse), having a transgene that or disorder of the colon. This method includes the steps of US 2006/0134109 A1 Jun. 22, 2006

(a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the colon. GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (b) contacting the GPCR polypep 0053. In either of these two methods, the mutation or tide with the candidate compound; and (c) measuring bio polymorphism is preferably associated with an alteration logical activity of the GPCR polypeptide in the transgenic (for example, a decrease) in the biological activity of the non-human mammal, wherein altered biological activity, polypeptide. relative to that of the transgenic non-human mammal not 0054. In another aspect, the invention features another contacted with the compound, indicates that the candidate method for determining whether a patient has an increased compound may be useful for the treatment of a disease or risk for developing a disease or disorder of the colon. The disorder of the colon. method includes measuring biological activity of a GPCR 0.048. In still another aspect, the invention features polypeptide from the patient that is substantially identical to another method for determining whether a candidate com a polypeptide listed in Tables 16 and 33, wherein increased pound may be useful for the treatment of a disease or or decreased levels in the GPCR biological activity, relative disorder of the colon. This method includes (a) providing a to normal levels, indicate that the patient may have an nucleic acid molecule comprising a promoter from a gene increased risk for developing a disease or disorder of the encoding a GPCR polypeptide listed in Tables 16 and 33, the colon. promoter operably linked to a reporter system; (b) contact 0055. In still another aspect, the invention features yet ing the nucleic acid molecule with the candidate compound; another method for determining whether a patient has an and (c) measuring reporter activity, wherein altered reporter increased risk for developing a disease or disorder of the activity, relative to a nucleic acid molecule not contacted colon. The method includes the step of measuring the with the compound, indicates that the candidate compound patient’s expression levels of a polypeptide listed in Tables may be useful for the treatment of a disease or disorder of 16 and 33, wherein altered levels in the expression, relative the colon. to normal, indicate that the patient has an increased risk for 0049. In another aspect, the invention features yet developing a disease or disorder of the colon. Preferably, the another method for determining whether a candidate com expression levels are determined by measuring levels of pound may be useful for the treatment of a disease or polypeptide or mRNA. disorder of the colon. This method includes the steps of: (a) providing a GPCR polypeptide substantially identical to a 0056 Diseases of the colon that can be treated or diag polypeptide listed in Tables 16 and 33; (b) contacting the nosed using the methods of the invention or for which polypeptide with the candidate compound; and (c) measur candidate therapeutic compounds may be identified include ing interaction of the candidate compound to the polypep acute self-limited infectious colitis, adenocarcinoma, tide. Interaction of the compound to the polypeptide indi adenoma, adenoma-carcinoma sequence, adenomatous cates that the candidate compound may be useful for the polyposis coli, adenosquamous carcinomas, allergic (eosi treatment of a disease or disorder of the colon. nophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb 0050. In still another aspect, the invention features nevus syndrome, brown bowel syndrome, Campylobacter another method for determining whether a candidate com fetus infection, carcinoid tumors, carcinoma of the anal pound may be useful for the treatment of a disease or canal, carcinoma of the colon and rectum, chlamidial proc disorder of the colon. This method includes (a) providing a titis, Crohn's disease, clear cell carcinomas, Clostridium GPCR polypeptide substantially identical to a polypeptide difficile pseudomembranous enterocolitis, collagenous coli listed in Tables 16 and 33; (b) contacting the polypeptide tis, colonic adenoma, colonic diverticulosis, colonic inertia, with the candidate compound; and (c) measuring the half colonic ischemia, congenital atresia, congenital megacolon life of the polypeptide, wherein an alteration in the half-life (Hirschsprung's disease), congenital Stenosis, constipation, of the polypeptide, relative to that of the polypeptide not Cowden's syndrome, cystic fibrosis, cytomegalovirus coli contacted with the compound, indicates that the candidate tis, diarrhea, dieulafor lesion, diversion colitis, diverticulitis, compound may be useful for the treatment of a disease or diverticulosis, drug-induced diseases, dysplasia and malig disorder of the colon. Preferably the GPCR polypeptide is in nancy in inflammatory bowel disease, Ehlers-Danlos Syn a cell or a cell free assay system. dromes, enterobiasis, familial adenomatous polyposis, familial polyposis syndromes, Gardner's syndrome, gas 0051. In another aspect, the invention features a method trointestinal stromal neoplasms, hemangiomas and vascular for determining whether a patient has an increased risk for anomalies, hemorrhoids, hereditary hemorrhagic telang developing a disease or disorder of the colon. The method iectasia, herpes colitis, hyperplastic polyps, idiopathic includes the step of determining whether the patient has a inflammatory bowel disease, incontinence, inflammatory mutation in a gene encoding a polypeptide listed in Tables bowel syndrome, inflammatory polyps, inherited adenoma 16 and 33, wherein presence of the mutation indicates that tous polyposis syndromes, intestinal hamartomas, intestinal the patient has an increased risk for developing a disease or pseudo-obstruction, irritable bowel syndrome, ischemic disorder of the colon. colitis, juvenile polyposis, juvenile polyps, Klippel 0.052 In a related aspect, the invention features another Trénaunay-Weber syndrome, leiomyomas, lipomas, lym method for determining whether a patient has an increased phocytic (microscopic) colitis, lymphoid hyperplasia and risk for developing a disease or disorder of the colon. This lymphoma, malaknock outplakia, malignant lymphoma, method includes the step of determining whether the patient malignant neoplasms, malrotation, metastatic neoplasms, has a polymorphism in a gene encoding a polypeptide listed mixed hyperplastic and adenomatous polyps, mucosal pro in Tables 16 and 33, wherein presence of the polymorphism lapse syndrome, neonatal necrotizing enterocolitis, neuroen US 2006/0134109 A1 Jun. 22, 2006

docrine cell tumors, neurogenic tumors, neutropenic entero tical to a polypeptide listed in Tables 17 and 33; (b) colitis, non-neoplastic polyps, Peutz-Jeghers syndrome, contacting the transgenic non-human mammal with the pneumatosis cystoides intestinalis, polyposis coli, candidate compound, and (c) measuring biological activity pseudomembranous colitis, pseudoxanthoma elasticum, of the GPCR polypeptide in the transgenic non-human pure squamous carcinomas, radiation colitis, Schistosomia mammal, wherein altered biological activity, relative to that sis, Shigella colitis (baciliary dysentery), spindle cell car of the transgenic non-human mammal not contacted with the cinomas, Spirochetosis, Stercolar ulcers, stromal tumors, compound, indicates that the candidate compound may be systemic sclerosis and CREST syndrome, trichuriasis, tubu useful for the treatment of a cardiovascular disease or lar adenoma (adenomatous polyp, polypoid adenoma), Tur disorder. cot's syndrome, Turner's syndrome, ulcerative colitis, vil 0065. In yet another aspect, the invention features a lous adenoma, and Volvulus. method for determining whether a candidate compound is a 0057. In another aspect, the invention features a non compound that may be useful for the treatment of a cardio human mammal (e.g., a mouse), having a transgene that vascular disease or disorder. This method includes the steps includes a nucleic acid molecule encoding a GPCR polypep of (a) providing a transgenic non-human mammal (e.g., a tide substantially identical to a polypeptide listed in Table mouse) overexpressing a nucleic acid molecule encoding a 16. GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (b) contacting the transgenic 0.058. In yet another aspect, the invention features a non-human mammal with the candidate compound; and (c) non-human mammal (e.g., a mouse), having a mutation in a measuring biological activity of the GPCR polypeptide in nucleic acid molecule encoding a GPCR polypeptide sub the transgenic non-human mammal, wherein altered biologi stantially identical to a polypeptide listed in Table 16. cal activity, relative to that of the transgenic non-human 0059. In a related aspect, the invention features a cell mammal not contacted with the compound, indicates that the from a non-human mammal having a transgene that includes candidate compound may be useful for the treatment of a a nucleic acid molecule encoding a GPCR polypeptide cardiovascular disease or disorder. substantially identical to a polypeptide listed in Table 16. 0066. In still another aspect, the invention features another method for determining whether a candidate com 0060. In another aspect, the invention features a cell from pound may be useful for the treatment of a cardiovascular a non-human mammal having a mutation in a nucleic acid disease or disorder. This method includes (a) providing a molecule encoding a GPCR polypeptide substantially iden nucleic acid molecule comprising a promoter from a gene tical to a polypeptide listed in Table 16. encoding a GPCR polypeptide listed in Tables 17 and 33, the 0061. In another aspect, the invention features a method promoter operably linked to a reporter system; (b) contact of preventing or treating cardiovascular disease, including ing the nucleic acid molecule with the candidate compound; introducing into a human an expression vector that includes and (c) measuring reporter activity, wherein altered reporter a nucleic acid molecule encoding a GPCR polypeptide activity, relative to a nucleic acid molecule not contacted substantially identical to a polypeptide listed in Tables 17 with the compound, indicates that the candidate compound and 33, operably linked to a promoter. may be useful for the treatment of a cardiovascular disease or disorder. 0062. In still another aspect, the invention features a method of treating or preventing cardiovascular disease, 0067. In another aspect, the invention features yet including administering to an animal (e.g., a human) a another method for determining whether a candidate com compound that modulates the biological activity of a GPCR pound may be useful for the treatment of a cardiovascular disease or disorder. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a Tables 17 and 33. polypeptide listed in Tables 17 and 33; (b) contacting the 0063. In yet another aspect, the invention features a polypeptide with the candidate compound; and (c) measur method for determining whether a candidate compound is a ing interaction of the candidate compound to the polypep compound that may be useful for the treatment of a cardio tide. Interaction of the compound to the polypeptide indi vascular disease or disorder. This method includes the steps cates that the candidate compound may be useful for the of (a) providing a GPCR polypeptide substantially identical treatment of a cardiovascular disease or disorder. to a polypeptide listed in Tables 17 and 33; (b) contacting the 0068. In still another aspect, the invention features GPCR polypeptide with the candidate compound; and (c) another method for determining whether a candidate com measuring biological activity of the GPCR polypeptide, pound may be useful for the treatment of a cardiovascular wherein altered biological activity, relative to that of the disease or disorder. This method includes (a) providing a GPCR polypeptide not contacted with the compound, indi GPCR polypeptide substantially identical to a polypeptide cates that the candidate compound may be useful for the listed in Tables 17 and 33; (b) contacting the polypeptide treatment of a cardiovascular disease or disorder. The GPCR with the candidate compound; and (c) measuring the half polypeptide can be in a cell or in a cell-free assay system. life of the polypeptide, wherein an alteration in the half-life 0064. In yet another aspect, the invention features a of the polypeptide, relative to that of the polypeptide not method for determining whether a candidate compound is a contacted with the compound, indicates that the candidate compound that may be useful for the treatment of a cardio compound may be useful for the treatment of a cardiovas vascular disease or disorder. This method includes the steps cular disease or disorder. Preferably the GPCR polypeptide of (a) providing a transgenic non-human mammal (e.g., a is in a cell or a cell free assay system. knock-out mouse) having a disruption in a nucleic acid 0069. In another aspect, the invention features a method molecule encoding a GPCR polypeptide substantially iden for determining whether a patient has an increased risk for US 2006/0134109 A1 Jun. 22, 2006

developing a cardiovascular disease or disorder. The method of the great arteries, congestive heart failure, constrictive includes the step of determining whether the patient has a pericarditis, cor pulmonale, coronary artery origin from mutation in a gene encoding a polypeptide listed in Tables pulmonary artery, coronary atherosclerosis, dilated (conges 17 and 33, wherein presence of the mutation indicates that tive) cardiomyopathy, diphtheria, double inlet left ventricle, the patient may have an increased risk for developing a double outlet right ventricle, Ebstein's malformation, cardiovascular disease or disorder. endocardial fibroelastosis, endocarditis, endomyocardial fibrosis, eosinophilic endomyocardial disease (Loffler 0070. In a related aspect, the invention features another endocarditis), fibroma, glycogen storage diseases, hemo method for determining whether a patient has an increased chromatosis, hypertensive heart disease, hyperthyroid heart risk for developing a cardiovascular disease or disorder. This disease, hypertrophic cardiomyopathy, hypothyroid heart method includes the step of determining whether the patient disease, idiopathic dilated cardiomyopathy, idiopathic myo has a polymorphism in a gene encoding a polypeptide listed carditis, infectious myocarditis, infective endocarditis, in Tables 17 and 33, wherein presence of the polymorphism ischemic heart disease, left ventricular failure, Libman indicates that the patient may have an increased risk for Sachs endocarditis, lupus erythematosus, lyme disease, developing a cardiovascular disease or disorder. marantic endocarditis, metastatic tumors, mitral insuffi 0071. In either of these two methods, the mutation or ciency, mitral regurgitation, mitral Stenosis, mitral valve polymorphism is preferably associated with an alteration prolapse, mucopolysaccharidoses, multifocal atrial tachy (for example, a decrease) in the biological activity of the cardia, myocardial infarction, myocardial ischemia, myo polypeptide. cardial rupture, myocarditis, myxomatuos degeneration, nonatheromatous coronary artery disease, nonbacterial 0072. In another aspect, the invention features another thrombotic endocarditis, noninfectious acute pericarditis, method for determining whether a patient has an increased nonviral infectious pericarditis, oblitaerative cardiomyopa risk for developing a cardiovascular disease or disorder. The thy, patent ductus arteriosus, pericardial effusion, pericardial method includes measuring biological activity of a GPCR tumors, pericarditis, persistent truncus arteriosis, premature polypeptide from the patient that is substantially identical to Ventricular contraction, progressive infarction, pulmonary a polypeptide listed in Tables 17 and 33, wherein increased atresia with intact ventricular septum, pulmonary atresia or decreased levels in the GPCR biological activity, relative with Vertricular septal defect, pulmonary insufficiency, pull to normal levels, indicate that the patient may have an monary regurgitation, pulmonary Stenosis, pulmonary valve increased risk for developing a cardiovascular disease or lesions, pulmonary valve Stenosis, pyogenic pericarditis, Q disorder. fever, radiations myocarditis, restrictive cardiomyopathy, 0073. In still another aspect, the invention features yet rhabdomyoma, rheumatic aortic Stenosis, rheumatic heart another method for determining whether a patient has an disease, rocky mountain spotted fever, rupture of the aortic increased risk for developing a cardiovascular disease or valve, sarcoid myocarditis, Scleroderma, shingolipidoses, disorder. The method includes the step of measuring the sinus brachycardia, Sudden death syndrome, syphilis, sys patient’s expression levels of a polypeptide listed in Tables temic embolism from mural thrombi, Systemic lupus etythe 17 and 33, wherein altered levels in the expression, relative matosus, tetralogy of fallot, thiamine deficiency (Beriberi) to normal, indicate that the patient has an increased risk for heart disease, thoracic outlet syndrome, Torsade de Pointes, developing a cardiovascular disease or disorder. Preferably, toxic cardiomyopathy, toxic myocarditis, toxoplasmosis, the expression levels are determined by measuring levels of trichinosis, tricuspid atresia, tricuspid insufficiency, tricus polypeptide or mRNA. pid regurgitation, tricuspid stenosis, tricuspid valve lesions, tuberculuos pericarditis, typhus, Ventricular aneurysm, ven 0074. One preferred cardiovascular disease that can be treated or diagnosed using the methods of the invention or tricular fibrillation, ventricular septal defect, ventricular for which candidate therapeutic compounds may be identi tachycardia, Ventriculoarterial septal defect, viral pericardi fied is coronary artery disease. Others include acute coro tis, and Wolff-Parkinson-White syndrome. nary syndrome, acute idiopathic pericarditis, acute rheu 0075. In another aspect, the invention features a non matic fever, American trypanosomiasis (Chagas disease), human mammal (e.g., a mouse), having a transgene that angina pectoris, ankylosing spondylitis, anomalous pulmo includes a nucleic acid molecule encoding a GPCR polypep nary venous connection, anomalous pulmonary venous tide substantially identical to a polypeptide listed in Table drainage, aortic atresia, aortic regurgitation, aortic Stenosis, 17. aortic valve insufficiency, aortopulmonary septal defect, 0076. In yet another aspect, the invention features a asymmetric septal hypertrophy, asystole, atrial fibrillation, non-human mammal (e.g., a mouse), having a mutation in a atrial flutter, atrial septal defect, atrioventricular septal nucleic acid molecule encoding a GPCR polypeptide sub defect, autoimmune myocarditis, bacterial endocarditis, cal stantially identical to a polypeptide listed in Table 17. cific aortic Stenosis, calcification of the cental valve, calci fication of the valve ring, carcinoid heart disease, cardiac 0077. In a related aspect, the invention features a cell amyloidosis, cardiac arrest, cardiac arrhythmia, cardiac fail from a non-human mammal having a transgene that includes ure, cardiac myxoma, cardiac rejection, cardiac tamponade, a nucleic acid molecule encoding a GPCR polypeptide cardiogenic shock, cardiomyopathy of pregnancy, chronic substantially identical to a polypeptide listed in Table 17. adhesive pericarditis, chronic constrictive pericarditis, 0078. In another aspect, the invention features a cell from chronic left ventricular failure, coarctation of the aorta, a non-human mammal having a mutation in a nucleic acid complete heart block, complete transposition of the great molecule encoding a GPCR polypeptide substantially iden vessels, congenital bicuspid aortic valves, congenital nar tical to a polypeptide listed in Table 17. rowing of the left ventricular outflow tract, congenital pull 0079. In another aspect, the invention features a method monary valve Stenosis, congenitally corrected transposition of preventing or treating a disease of the intestine including US 2006/0134109 A1 Jun. 22, 2006 introducing into a human an expression vector that includes and (c) measuring reporter activity, wherein altered reporter a nucleic acid molecule encoding a GPCR polypeptide activity, relative to a nucleic acid molecule not contacted substantially identical to a polypeptide listed in Tables 18 with the compound, indicates that the candidate compound and 33, operably linked to a promoter. may be useful for the treatment of a disease or disorder of 0080. In still another aspect, the invention features a the intestine. method of treating or preventing a disease of the intestine 0085. In another aspect, the invention features yet including administering to an animal (e.g., a human) a another method for determining whether a candidate com compound that modulates the biological activity of a GPCR pound may be useful for the treatment of a disease or polypeptide Substantially identical to a polypeptide listed in disorder of the intestine. This method includes the steps of: Tables 18 and 33. (a) providing a GPCR polypeptide substantially identical to 0081. In yet another aspect, the invention features a a polypeptide listed in Tables 18 and 33; (b) contacting the method for determining whether a candidate compound is a polypeptide with the candidate compound; and (c) measur compound that may be useful for the treatment of a disease ing interaction of the candidate compound to the polypep or disorder of the intestine. This method includes the steps tide. Interaction of the compound to the polypeptide indi of (a) providing a GPCR polypeptide substantially identical cates that the candidate compound may be useful for the to a polypeptide listed in Tables 18 and 33; (b) contacting the treatment of a disease or disorder of the intestine. GPCR polypeptide with the candidate compound; and (c) 0086. In still another aspect, the invention features measuring biological activity of the GPCR polypeptide, another method for determining whether a candidate com wherein altered biological activity, relative to that of the pound may be useful for the treatment of a disease or GPCR polypeptide not contacted with the compound, indi disorder of the intestine. This method includes (a) providing cates that the candidate compound may be useful for the a GPCR polypeptide substantially identical to a polypeptide treatment of a disease or disorder of the intestine. The GPCR listed in Tables 18 and 33; (b) contacting the polypeptide polypeptide can be in a cell or in a cell-free assay system. with the candidate compound; and (c) measuring the half 0082 In yet another aspect, the invention features a life of the polypeptide, wherein an alteration in the half-life method for determining whether a candidate compound is a of the polypeptide, relative to that of the polypeptide not compound that may be useful for the treatment of a disease contacted with the compound, indicates that the candidate or disorder of the intestine. This method includes the steps compound may be useful for the treatment of a disease or of (a) providing a transgenic non-human mammal (e.g., a disorder of the intestine. Preferably the GPCR polypeptide knock-out mouse) having a disruption in a nucleic acid is in a cell or a cell free assay system. molecule encoding a GPCR polypeptide substantially iden 0087. In another aspect, the invention features a method tical to a polypeptide listed in Tables 18 and 33; (b) for determining whether a patient has an increased risk for contacting the transgenic non-human mammal with the developing a disease or disorder of the intestine. The method candidate compound; and (c) measuring biological activity includes the step of determining whether the patient has a of the GPCR polypeptide in the transgenic non-human mutation in a gene encoding a polypeptide listed in Tables mammal, wherein altered biological activity, relative to that 18 and 33, wherein presence of the mutation indicates that of the transgenic non-human mammal not contacted with the the patient may have an increased risk for developing a compound, indicates that the candidate compound may be disease or disorder of the intestine. useful for the treatment of a disease or disorder of the 0088. In a related aspect, the invention features another intestine. method for determining whether a patient has an increased 0083. In yet another aspect, the invention features a risk for developing a disease or disorder of the intestine. This method for determining whether a candidate compound is a method includes the step of determining whether the patient compound that may be useful for the treatment of a disease has a polymorphism in a gene encoding a polypeptide listed or disorder of the intestine. This method includes the steps in Tables 18 and 33, wherein presence of the polymorphism of (a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the intestine. GPCR polypeptide substantially identical to a polypeptide 0089. In either of these two methods, the mutation or listed in Tables 18 and 33; (b) contacting the transgenic polymorphism is preferably associated with an alteration non-human mammal with the candidate compound; and (c) (for example, a decrease) in the biological activity of the measuring biological activity of the GPCR polypeptide in polypeptide. the transgenic non-human mammal, wherein altered biologi cal activity, relative to that of the transgenic non-human 0090. In another aspect, the invention features another mammal not contacted with the compound, indicates that the method for determining whether a patient has an increased candidate compound may be useful for the treatment of a risk for developing a disease or disorder of the intestine. The disease or disorder of the intestine. method includes measuring biological activity of a GPCR 0084. In still another aspect, the invention features polypeptide from the patient that is substantially identical to another method for determining whether a candidate com a polypeptide listed in Tables 18 and 33, wherein increased pound may be useful for the treatment of a disease or or decreased levels in the GPCR biological activity, relative disorder of the intestine. This method includes (a) providing to normal levels, indicate that the patient may have an a nucleic acid molecule comprising a promoter from a gene increased risk for developing a disease or disorder of the encoding a GPTR polypeptide listed in Tables 18 and 33, the intestine. promoter operably linked to a reporter system; (b) contact 0091. In still another aspect, the invention features yet ing the nucleic acid molecule with the candidate compound; another method for determining whether a patient has an US 2006/0134109 A1 Jun. 22, 2006 increased risk for developing a disease or disorder of the 0093. In another aspect, the invention features a non intestine. The method includes the step of measuring the human mammal (e.g., a mouse), having a transgene that patient’s expression levels of a polypeptide listed in Tables includes a nucleic acid molecule encoding a GPCR polypep 18 and 33, wherein altered levels in the expression, relative tide substantially identical to a polypeptide listed in Table to normal, indicate that the patient has an increased risk for 18. developing a disease or disorder of the intestine. Preferably, 0094. In yet another aspect, the invention features a the expression levels are determined by measuring levels of non-human mammal (e.g., a mouse), having a mutation in a polypeptide or mRNA. nucleic acid molecule encoding a GPCR polypeptide sub 0092 Diseases of the intestine that can be treated or stantially identical to a polypeptide listed in Table 18. diagnosed using the methods of the invention or for which 0095. In a related aspect, the invention features a cell candidate therapeutic compounds may be identified include from a non-human mammal having a transgene that includes abdominal hernia, abetalipoproteinemia, abnormal rotation, a nucleic acid molecule encoding a GPCR polypeptide acute hypotensive hypoperfusion, acute intestinal ischemia, substantially identical to a polypeptide listed in Table 18. acute Small intestinal infarction, adenocarcinoma, adenoma, 0096. In another aspect, the invention features a cell from adhesions, amebiasis, anemia, arterial occlusion, atypical a non-human mammal having a mutation in a nucleic acid mycobacteriosis, bacterial diarrhea, bacterial overgrowild molecule encoding a GPCR polypeptide substantially iden typeh Syndromes, botulism, Campylobacter fetus infection, tical to a polypeptide listed in Table 18. Campylobacter jejuni, carbohydrate absorption defects, car cinoid tumors, celiac disease (nontropical sprue, gluten 0097. In another aspect, the invention features a method induced enteropathy), cholera, Chrohn's disease, chronic of preventing or treating a disease of the kidney including intestinal ischemia, Clostridium difficile pseudomembra introducing into a human an expression vector that includes nous enterocolitis, Clostridium perfiringens, congenital a nucleic acid molecule encoding a GPCR polypeptide umbilical hernia, Cronkhite-Canada syndrome, cytomega substantially identical to a polypeptide listed in Tables 19 lovirus enterocolitis, diarrhea, diarrhea caused by invasive and 33, operably linked to a promoter. bacteria, diverticulitits, diverticulosis, dysentery, enteroin 0098. In still another aspect, the invention features a vasive and enterohemorrhagic Escherichia coli infection, method of treating or preventing a disease of the kidney eosinophilic gastroenteritis, failure of peristalsis, familial including administering to an animal (e.g., a human) a polyposis Syndromes, food poisoning, fungal enteritis, gan compound that modulates the biological activity of a GPCR gliocytic paragangliomas, Gardner's syndrome, gastrointes polypeptide Substantially identical to a polypeptide listed in tinal stromal neoplasms, giardiasis, hemorroids, hernia, Tables 19 and 33. hyperplastic polyps, idiopathic inflammatory bowel disease, illeus, imperforate anus, intestinal (abdominal ischemia), 0099. In yet another aspect, the invention features a intestinal atresia, intestinal cryptosporidiosis, microsporidi method for determining whether a candidate compound is a osis & isosporiasis in AIDS, intestinal hamartomas, intesti compound that may be useful for the treatment of a disease nal helminthiasis, intestinal hemorrhage, intestinal infiltra or disorder of the kidney. This method includes the steps of tive disorders, intestinal lymphangiectasia, intestinal (a) providing a GPCR polypeptide substantially identical to obstruction, intestinal perforation, intestinal reduplication, a polypeptide listed in Tables 19 and 33; (b) contacting the intestinal Stenosis, intestinal tuberculosis, intussusception, GPCR polypeptide with the candidate compound; and (c) jejunal diverticulosis, juvenile polyposis, juvenile retention measuring biological activity of the GPCR polypeptide, polyps, lactase deficiency, lymphomas, malabsorption syn wherein altered biological activity, relative to that of the drome, malignant lymphoma, malignant neoplasms, malro GPCR polypeptide not contacted with the compound, indi tations, mechanical obstruction, Meckel's diverticulum, cates that the candidate compound may be useful for the meconium ileus, mediterranean lymphoma, mesenchymal treatment of a disease or disorder of the kidney. The GPCR tumors, mesenteric vasculitis, mesenteric vein thrombosis, polypeptide can be in a cell or in a cell-free assay system. metastatic neoplasms, microVillus inclusion disease, mixed 0100. In yet another aspect, the invention features a hyperplastic and adenomatous polyps, neonatal necrotizing method for determining whether a candidate compound is a enterocolitis, nodular duodenum, nonocclusive intestinal compound that may be useful for the treatment of a disease ischemia, nonspecific duodenitis, nontyphoidal salmonello or disorder of the kidney. This method includes the steps of sis, omphalocele, parasitic infections, peptic ulcer disease, (a) providing a transgenic non-human mammal (e.g., a Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, knock-out mouse) having a disruption in a nucleic acid poorly differentiated neuroendocrine carcinomas, primary molecule encoding a GPCR polypeptide substantially iden lymphoma, protein-losing enteropathy, Salmonella gastro tical to a polypeptide listed in Tables 19 and 33; (b) enteritis, sarcoidosis, sarcomas, Shigellosis, staphlococcal contacting the transgenic non-human mammal with the food poisoning, Steatorrhea, Sugar intolerance, thrombosis of candidate compound; and (c) measuring biological activity the mesenteric veins, toxigenic diarrhea, toxigenic Escheri of the GPCR polypeptide in the transgenic non-human chia coli infection, tropical sprue, tubular adenoma mammal, wherein altered biological activity, relative to that (adenomatous polyp, polypoid adenoma), typhoid fever, of the transgenic non-human mammal not contacted with the ulcers, vascular malformations, Villous adenoma, viral compound, indicates that the candidate compound may be enteritis, viral gastroenteritis, visceral myopathy, visceral useful for the treatment of a disease or disorder of the neuropathy, Vitelline duct remnants, volvulus, Western-type kidney. intestinal lymphoma, Whipple's disease (intestinal lipopy strophy), Yersinia enterocolitica & Yersinia pseudotubercu 0101. In yet another aspect, the invention features a losis infection, and Zollinger-Ellison syndrome. method for determining whether a candidate compound is a US 2006/0134109 A1 Jun. 22, 2006

compound that may be useful for the treatment of a disease has a polymorphism in a gene encoding a polypeptide listed or disorder of the kidney. This method includes the steps of in Tables 19 and 33, wherein presence of the polymorphism (a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the kidney. GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (b) contacting the transgenic 0.107. In either of these two methods, the mutation or non-human mammal with the candidate compound; and (c) polymorphism is preferably associated with an alteration measuring biological activity of the GPCR polypeptide in (for example, a decrease) in the biological activity of the the transgenic non-human mammal, wherein altered biologi polypeptide. cal activity, relative to that of the transgenic non-human 0108. In another aspect, the invention features another mammal not contacted with the compound, indicates that the method for determining whether a patient has an increased candidate compound may be useful for the treatment of a risk for developing a disease or disorder of the kidney. The disease or disorder of the kidney. method includes measuring biological activity of a GPCR 0102) In still another aspect, the invention features polypeptide from the patient that is substantially identical to another method for determining whether a candidate com a polypeptide listed in Tables 19 and 33, wherein increased pound may be useful for the treatment of a disease or or decreased levels in the GPCR biological activity, relative disorder of the kidney. This method includes (a) providing a to normal levels, indicate that the patient may have an nucleic acid molecule comprising a promoter from a gene increased risk for developing a disease or disorder of the encoding a GPCR polypeptide listed in Tables 19 and 33, the kidney. promoter operably linked to a reporter system; (b) contact 0.109. In still another aspect, the invention features yet ing the nucleic acid molecule with the candidate compound; another method for determining whether a patient has an and (c) measuring reporter activity, wherein altered reporter increased risk for developing a disease or disorder of the activity, relative to a nucleic acid molecule not contacted kidney. The method includes the step of measuring the with the compound, indicates that the candidate compound patient’s expression levels of a polypeptide listed in Tables may be useful for the treatment of a disease or disorder of 19 and 33, wherein altered levels in the expression, relative the kidney. to normal, indicate that the patient has an increased risk for 0103) In another aspect, the invention features yet developing a disease or disorder of the kidney. Preferably, another method for determining whether a candidate com the expression levels are determined by measuring levels of pound may be useful for the treatment of a disease or polypeptide or mRNA. disorder of the kidney. This method includes the steps of: (a) providing a GPCR polypeptide substantially identical to a 0110 Diseases of the kidney that can be treated or polypeptide listed in Tables 19 and 33; (b) contacting the diagnosed using the methods of the invention or for which polypeptide with the candidate compound; and (c) measur candidate therapeutic compounds may be identified include ing interaction of the candidate compound to the polypep acquired cystic disease, acute (postinfectious) glomerulone phritis, acute infectious interstitial nephritis, acute intersti tide. Interaction of the compound-to the polypeptide indi tial nephritis, acute pyelonephritis, acute renal failure, acute cates that the candidate compound may be useful for the transplant failure, acute tubular necrosis, adult polycystic treatment of a disease or disorder of the kidney. kidney disease, AL amyloid, analgesic nephropathy, anti 0104. In still another aspect, the invention features glomerular basement membrane disease (Goodpasture's another method for determining whether a candidate com Syndrome), asymptomatic hematuria, asymptomatic pro pound may be useful for the treatment of a disease or teinuria, autosomal dominant polycystic kidney disease, disorder of the kidney. This method includes (a) providing a autosomal recessive polycystic kidney disease, Bence Jones GPCR polypeptide substantially identical to a polypeptide cast nephropathy, benign familial hematuria, benign neph listed in Tables 19 and 33; (b) contacting the polypeptide rosclerosis and atheromatous embolization, bilateral cortical with the candidate compound; and (c) measuring the half necrosis, chronic glomerulonephritis, chronic interstitial life of the polypeptide, wherein an alteration in the half-life nephritis, chronic pyelonephritis, chronic renal failure, of the polypeptide, relative to that of the polypeptide not chronic transplant failure, circulating immune complex contacted with the compound, indicates that the candidate nephritis, crescentic glomerulonephritis, cryoglobulinemia, compound may be useful for the treatment of a disease or cystic renal dysplasia, diabetic glomerulosclerosis, diabetic disorder of the kidney. Preferably the GPCR polypeptide is nephropathy, dialysis cystic disease, drug induced (allergic) in a cell or a cell free assay system. acute interstitial nephritis, ectopic kidney, Fabry's disease, familial juvenile nephronophthisis-medullary cystic disease 0105. In another aspect, the invention features a method complex, focal glomerulosclerosis (segmental hyalinosis), for determining whether a patient has an increased risk for glomerulocystic disease, glomerulonephritis, glomerulone developing a disease or disorder of the kidney. The method phritis associated with bacterial endocarditis, glomerulo includes the step of determining whether the patient has a Sclerosis, hemolytic-uremic syndrome, Henoch-Schönlein mutation in a gene encoding a polypeptide listed in Tables purpura, hepatitis-associated glomerulonephritis, hereditary 19 and 33, wherein presence of the mutation indicates that nephritis (Alport syndrome), horseshoe kidney, hydroneph the patient may have an increased risk for developing a rosis, IgA nephropathy, infantile polycystic kidney disease, disease or disorder of the kidney. ischemic acute tubular necrosis, light-cahin deposit disease, 0106. In a related aspect, the invention features another malignant nephrosclerosis, medullary cystic disease, mem method for determining whether a patient has an increased branoproliferative (mesangiocapillary) glomerulonephritis, risk for developing a disease or disorder of the kidney. This membranous glomerulonephritis, membranous nephropathy, method includes the step of determining whether the patient mesangial proliferative glorierulonephritis (includes Berg US 2006/0134109 A1 Jun. 22, 2006 er's Disease), minimal change glomerular disease, minimal 0118. In yet another aspect, the invention features a change nephrotic syndrome, nephritic syndrome, nephro method for determining whether a candidate compound is a blastoma (Wilms tumor), nephronophthisis (medullary cys compound that may be useful for the treatment of a disease tic disease complex), nephrotic syndrome, plasma cell dys or disorder of the liver. This method includes the steps of (a) crasias (monoclonal immunoglobulin-induced renal providing a transgenic non-human mammal (e.g., a knock damage), polyarteritis nodosa, proteinuria, pyelonephritis, out mouse) having a disruption in a nucleic acid molecule rapidly progressive (crescentic) glomerulonephritis, renal encoding a GPCR polypeptide substantially identical to a agenesis, renal amyloidosis, renal cell carcinoma, renal polypeptide listed in Tables 20 and 33; (b) contacting the dysgenesis, renal dysplasia, renal hypoplasia, renal infec transgenic non-human mammal with the candidate com tion, renal osteodystrophy, renal stones (urolithiasis), renal pound; and (c) measuring biological activity of the GPCR tubular acidosis, renal vasculitis, renovascular hypertension, polypeptide in the transgenic non-human mammal, wherein Scleroderma (progressive systemic Sclerosis), secondary altered biological activity, relative to that of the transgenic acquired glomerulonephritis, simple renal cysts, systemic non-human mammal not contacted with the compound, lupus erythematosus, thin basement membrane nephropathy, indicates that the candidate compound may be useful for the thrombotic microangiopathy, thrombotic thrombocytopenic treatment of a disease or disorder of the liver. purpura, toxic acute tubular necrosis, tubular defects, tubu lointerstitial disease in multiple myeloma, urate nephropa 0119). In yet another aspect, the invention features a thy, urinary obstruction, and vasculitis. method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease 0111. In another aspect, the invention features a non or disorder of the liver. This method includes the steps of (a) human mammal (e.g., a mouse), having a transgene that providing a transgenic non-human mammal (e.g., a mouse) includes a nucleic acid molecule encoding a GPCR polypep overexpressing a nucleic acid molecule encoding a GPCR tide substantially identical to a polypeptide listed in Table polypeptide Substantially identical to a polypeptide listed in 19. Tables 20 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring 0112 In yet another aspect, the invention features a biological activity of the GPCR polypeptide in the trans non-human mammal (e.g., a mouse), having a mutation in a genic non-human mammal, wherein altered biological activ nucleic acid molecule encoding a GPCR polypeptide sub ity, relative to that of the transgenic non-human mammal not stantially identical to a polypeptide listed in Table 19. contacted with the compound, indicates that the candidate 0113. In a related aspect, the invention features a cell compound may be useful for the treatment of a disease or from a non-human mammal having a transgene that includes disorder of the liver. a nucleic acid molecule encoding a GPCR polypeptide 0.120. In still another aspect, the invention features substantially identical to a polypeptide listed in Table 19. another method for determining whether a candidate com 0114. In another aspect, the invention features a cell from pound may be useful for the treatment of a disease or a non-human mammal having a mutation in a nucleic acid disorder of the liver. This method includes (a) providing a molecule encoding a GPCR polypeptide substantially iden nucleic acid molecule comprising a promoter from a gene tical to a polypeptide listed in Table 19. encoding a GPCR polypeptide listed in Tables 20 and 33, the promoter operably linked to a reporter system; (b) contact 0115) In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the liver including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 20 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the liver. 0116. In still another aspect, the invention features a 0.121. In another aspect, the invention features yet method of treating or preventing a disease of the liver another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the liver. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a Tables 20 and 33. polypeptide listed in Tables 20 and 33; (b) contacting the polypeptide with the candidate compound; and (c) measur 0117. In yet another aspect, the invention features a ing interaction of the candidate compound to the polypep method for determining whether a candidate compound is a tide. Interaction of the compound to the polypeptide indi compound that may be useful for the treatment of a disease cates that the candidate compound may be useful for the or disorder of the liver. This method includes the steps of (a) treatment of a disease or disorder of the liver. providing a GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (b) contacting the 0122) In still another aspect, the invention features GPCR polypeptide with the candidate compound; and (c) another method for determining whether a candidate com measuring biological activity of the GPCR polypeptide, pound may be useful for the treatment of a disease or wherein altered biological activity, relative to that of the disorder of the liver. This method includes (a) providing a GPCR polypeptide not contacted with the compound, indi GPCR polypeptide substantially identical to a polypeptide cates that the candidate compound may be useful for the listed in Tables 20 and 33; (b) contacting the polypeptide treatment of a disease or disorder of the liver. The GPCR with the candidate compound; and (c) measuring the half polypeptide can be in a cell or in a cell-free assay system. life of the polypeptide, wherein an alteration in the half-life US 2006/0134109 A1 Jun. 22, 2006 of the polypeptide, relative to that of the polypeptide not hemangioma, cholangiocarcinoma, cholangitic abcess, contacted with the compound, indicates that the candidate choleostasis, cholestatic viral hepatitis, chronic active hepa compound may be useful for the treatment of a disease or titis, chronic alcoholic liver disease, chronic graft-versus disorder of the liver. Preferably the GPCR polypeptide is in host disease, chronic hepatic venous congestion, chronic a cell or a cell free assay system. hepatitis, chronic liver failure, chronic passive congestion, chronic viral hepatitis, cirrhosis, combined hepatocellular 0123. In another aspect, the invention features a method and cholangiocarcinoma, confluent hepatic necrosis, con for determining whether a patient has an increased risk for genital hepatic fibrosis, Crigler-Najjar syndrome, cryptoge developing a disease or disorder of the liver. The method nic cirrhosis, cystic fibrosis, defects of coagulation, delta includes the step of determining whether the patient has a hepatitis, Dubin-Johnson syndrome, epithelioid heman mutation in a gene encoding a polypeptide listed in Tables gioendothelioma, erythrohepatic protoporphyria, extrahe 20 and 33, wherein presence of the mutation indicates that patic biliary obstruction (primary biliary cirrhosis), fatty the patient may have an increased risk for developing a change, fatty liver, focal necrosis, focal nodular hyperplasia, disease or disorder of the liver. fulminant viral hepatitis, galactosemia, Gilbert's syndrome, 0.124. In a related aspect, the invention features another glycogen storage diseases, graft-Versus-host disease, granu method for determining whether a patient has an increased lomatous hepatitis, hemangioma, hemangiosarcoma, hemo risk for developing a disease or disorder of the liver. This chromatosis, hepatic adenoma, hepatic amebiasis, hepatic method includes the step of determining whether the patient encephalopathy, hepatic failure, hepatic Schistosomiasis, has a polymorphism in a gene encoding a polypeptide listed hepatic veno-occlusive disease, hepatitis A, hepatitis B. in Tables 20 and 33, wherein presence of the polymorphism hepatitis C, hepatitis D. hepatitis E. hepatoblastoma, hepa indicates that the patient may have an increased risk for tocellular adenoma, hepatocellular carcinoma, hepatocellu developing a disease or disorder of the liver. lar necrosis, hepatorenal syndrome, hereditary fructose intolerance, hereditary hemochromatosis, herpesvirus hepa 0125. In either of these two methods, the mutation or titis, hydatid cust, hyperplastic lesions, hypoalbuminenia, polymorphism is preferably associated with an alteration infantile hemangioendothelioma, infarction of the liver, (for example, a decrease) in the biological activity of the infectious mononucleosis hepatitis, inflammatory pseudotu polypeptide. mor of the liver, intrahepatic cholangiocarcinoma, intrahe 0126. In another aspect, the invention features another patic cholestasis, intrahepatic protal hypertension, ischemic method for determining whether a patient has an increased necrosis (ischemic hepatitis), isoniazid-induced necrosis, risk for developing a disease or disorder of the liver. The jaundice, leptospirosis, liver cell adenoma, liver manifesta method includes measuring biological activity of a GPCR tions of Rocky Mountain spotted fever, macronodular cir polypeptide from the patient that is substantially identical to rhosis, macrovesicular steatosis, malignant vascular neo a polypeptide listed in Tables 20 and 33, wherein increased plasts, mass lesions, massive hepatocellular necrosis, or decreased levels in the GPCR biological activity, relative massive necrosis, mesenchymal hamartoma, metastatic tumors, micronodular cirrhosis, microvesicular Steatosis, to normal levels, indicate that the patient may have an neonatal (physiologic) jaundice, neonatal hepatitis, neoplas increased risk for developing a disease or disorder of the tic lesions, nodular transformation (nodular regenerative liver. hyperplasia, nonSuppurative infections, nutritional cirrhosis, 0127. In still another aspect, the invention features yet nutritional liver disease, oriental cholangiohepatitis, para another method for determining whether a patient has an sitic infestation of the liver, peliosis hepatis, porphyria increased risk for developing a disease or disorder of the cutaneo tarda, portal hypertension, portal vein thrombosis, liver. The method includes the step of measuring the posthepatic portal hypertension, predictiable (dose-related) patient’s expression levels of a polypeptide listed in Tables toxicity, prehepatic portal hypertension, primary biliary cir 20 and 33, wherein altered levels in the expression, relative rhosis, primary Sclerosing cholangitis, pyogenic liver to normal, indicate that the patient has an increased risk for abcess, Q-fever hepatitis, Rotor's syndrome, Sclerosing bile developing a disease or disorder of the liver. Preferably, the duct adenoma, Sclerosing cholangitis, secondary hemochro expression levels are determined by measuring levels of matosis, Submassive necrosis, syphilis, toxic liver injury, polypeptide or mRNA. tyrosinemia, undifferentiated sarcoma, unpredictable (idio 0128 Diseases of the liver that can be treated or diag syncratic) toxicity, vascular lesions, virus-induced cirrhosis, nosed using the methods of the invention or for which Wilson's disease, and Zonal necrosis. candidate therapeutic compounds may be identified include 0129. In another aspect, the invention features a non acute alcoholic hepatitis (acute Sclerosing hyaline necrosis human mammal (e.g., a mouse), having a transgene that of the liver), acute graft-versus-host disease, acute hepatitis, includes a nucleic acid molecule encoding a GPCR polypep acute hepatocellular injury associated with infectious dis tide substantially identical to a polypeptide listed in Table eases other than viral hepatitis... acute liver failure, acute 2O. viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cirrhosis, alcoholic hepatitis, alcoholic liver dis 0.130. In yet another aspect, the invention features a ease, alpha I-antitrypsin deficiency, amebic abscess, angi non-human mammal (e.g., a mouse), having a mutation in a olmyolipoma, angiosarcoma, ascending cholangitis, autoim nucleic acid molecule encoding a GPCR polypeptide sub mune chronic active hepatitis (lupoid hepatitis), bile duct stantially identical to a polypeptide listed in Table 20. adenoma, bile duct cystadenocarcinoma, bile duct cystad 0.131. In a related aspect, the invention features a cell enoma, biliary atresia, biliary cirrhosis, biliary papilloma from a non-human mammal having a transgene that includes tosis, bridging necrosis, Budd-Chiari Syndrome, Byler dis a nucleic acid molecule encoding a GPCR polypeptide ease, cardiac fibrosis of the liver, Caroli disease, cavernous substantially identical to a polypeptide listed in Table 20. US 2006/0134109 A1 Jun. 22, 2006

0132) In another aspect, the invention features a cell from disorder. This method includes (a) providing a nucleic acid a non-human mammal having a mutation in a nucleic acid molecule comprising a promoter from a gene encoding a molecule encoding a GPCR polypeptide substantially iden GPCR polypeptide listed in Tables 21 and 33, the promoter tical to a polypeptide listed in Table 20. operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) 0133. In another aspect, the invention features a method measuring reporter activity, wherein altered reporter activity, of preventing or treating lung disease, including introducing relative to a nucleic acid molecule not contacted with the into a human an expression vector that includes a nucleic acid molecule encoding a GPCR polypeptide substantially compound, indicates that the candidate compound may be identical to a polypeptide listed in Tables 21 and 33, oper useful for the treatment of a lung disease or disorder. ably linked to a promoter. 0.139. In another aspect, the invention features yet another method for determining whether a candidate com 0134. In still another aspect, the invention features a pound may be useful for the treatment of a lung disease or method of treating or preventing lung disease, including disorder. This method includes the steps of: (a) providing a administering to an animal (e.g., a human) a compound that GPCR polypeptide substantially identical to a polypeptide modulates the biological activity of a GPCR polypeptide listed in Tables 21 and 33; (b) contacting the polypeptide substantially identical to a polypeptide listed in Tables 21 with the candidate compound; and (c) measuring interaction and 33. of the candidate compound to the polypeptide. Interaction of 0135) In yet another aspect, the invention features a the compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a lung disease compound that may be useful for the treatment of a lung or disorder. disease or disorder. This method includes the steps of (a) 0140. In still another aspect, the invention features providing a GPCR polypeptide substantially identical to a another method for determining whether a candidate com polypeptide listed in Tables 21 and 33; (b) contacting the pound may be useful for the treatment of a lung disease or GPCR polypeptide with the candidate compound; and (c) disorder. This method includes (a) providing a GPCR measuring biological activity of the GPCR polypeptide, polypeptide Substantially identical to a polypeptide listed in wherein altered biological activity, relative to that of the Tables 21 and 33; (b) contacting the polypeptide with the GPCR polypeptide not contacted with the compound, indi candidate compound; and (c) measuring the half-life of the cates that the candidate compound may be useful for the polypeptide, wherein an alteration in the half-life of the treatment of a lung disease or disorder. The GPCR polypep polypeptide, relative to that of the polypeptide not contacted tide can be in a cell or in a cell-free assay system. with the compound, indicates that the candidate compound 0136. In yet another aspect, the invention features a may be useful for the treatment of a lung disease or disorder. method for determining whether a candidate compound is a Preferably, the GPCR polypeptide is in a cell or a cell free compound that may be useful for the treatment of a disease assay system. or disorder of the lung. This method includes the steps of (a) 0.141. In another aspect, the invention features a method providing a transgenic non-human mammal (e.g., a knock for determining whether a patient has an increased risk for out mouse) having a disruption in a nucleic acid molecule developing a lung disease or disorder. The method includes encoding a GPCR polypeptide substantially identical to a the step of determining whether the patient has a mutation in polypeptide listed in Tables 21 and 33; (b) contacting the a gene encoding a polypeptide listed in Tables 21 and 33. transgenic non-human mammal with the candidate com wherein presence of the mutation indicates that the patient pound; and (c) measuring biological activity of the trans may have an increased risk for developing a lung disease or genic non-human mammal, wherein altered biological activ disorder. ity, relative to that of the transgenic non-human mammal not 0142. In a related aspect, the invention features another contacted with the compound, indicates that the candidate method for determining whether a patient has an increased compound may be useful for the treatment of a disease or risk for developing a lung disease or disorder. This method disorder of the lung. includes the step of determining whether the patient has a 0137 In yet another aspect, the invention features a polymorphism in a gene encoding a polypeptide listed in method for determining whether a candidate compound is a Tables 21 and 33, wherein presence of the polymorphism compound that may be useful for the treatment of a disease indicates that the patient may have an increased risk for or disorder of the lung. This method includes the steps of (a) developing a lung disease or disorder. providing a transgenic non-human mammal (e.g., a mouse) 0.143. In either of these two methods, the mutation or overexpressing a nucleic acid molecule encoding a GPCR polymorphism is preferably associated with an alteration polypeptide Substantially identical to a polypeptide listed in (for example, a decrease) in the biological activity of the Tables 21 and 33; (b) contacting the transgenic non-human polypeptide. mammal with the candidate compound; and (c) measuring biological activity of the transgenic non-human mammal, 0144. In another aspect, the invention features another method for determining whether a patient has an increased wherein altered biological activity, relative to that of the risk for developing a lung disease or disorder. The method transgenic non-human mammal not contacted with the com includes measuring biological activity of a GPCR polypep pound, indicates that the candidate compound may be useful tide from the patient that is substantially identical to a for the treatment of a disease or disorder of the lung. polypeptide listed in Tables 21 and 33, wherein increased or 0138. In still another aspect, the invention features decreased levels in the GPCR biological activity, relative to another method for determining whether a candidate com normal levels, indicate that the patient may have an pound may be useful for the treatment of a lung disease or increased risk for developing a lung disease or disorder. US 2006/0134109 A1 Jun. 22, 2006

0145. In still another aspect, the invention features yet tal) emphysema, drug-induced asthma, drug-induced diffuse another method for determining whether a patient has an alveolar damage, dyspnea, ectopic hormone syndromes, increased risk for developing a lung disease or disorder. The emphysema, empyemma, eosinophilic pneumonias, exer method includes the step of measuring the patient’s expres cise-induced asthma, extralobar sequestration, extrinsic sion levels of a polypeptide listed in Tables 21 and 33, allergic asthma, fat emboli, focal dust emphysema, follicular wherein altered levels in the expression, relative to normal, bronchiolitis, follicular bronchitis, foreign-body embolism, indicate that the patient has an increased risk for developing Fuller's earth pneumoconiosis, functional resistance to arte a lung disease or disorder. Preferably, the expression levels rial flow (vasoconstriction), fungal granulomas of the lung, are determined by measuring levels of polypeptide or fungal infections, Goodpasture’s syndrome, graphite pneu mRNA. moconiosis, gray hepatization, hamartomas, hard metal dis 0146 Preferred lung diseases (including those of the ease, hemoptysis, hemothorax, herniation of lung tissue, traches) that can be treated or diagnosed using the methods herpes simplex, heterotopic tissues, high-altitude pulmonary of the invention or for which candidate therapeutic com edema, histoplasmosis, horseshoe lung, humidifier fever, pounds may be identified include abnormal diffusion, abnor hyaline membrane disease, hydatid cysts, hydrothorax, mal perfusion, abnormal ventilation, accelerated silicosis, hypersensitivity pneumonitis (extrinsic allergic alveolitis), actinomycosis, acute air space pneumonia (acute bacterial hypoxic vascular remodeling, iatrogenic drug-, chemical-, or pneumonia), acute bronchiolitis, acute congestion, acute radiation-induced interstitial fibrosis, idiopathic interstitial infections of the lung, acute interstitial pneumonia, acute pneumonia, idiopathic organizing pneumonia, idiopathic necrotizing viral pneumonia, acute organic dust toxic syn pulmonary fibrosis (fibrosing alveolitis, Hamman-Rich syn drome, acute pneumonia, acute radiation pneumonitis, acute drome, acute interstitial pneumonia), idiopathic pulmonary rheumatic fever, acute silicosis, acute tracheobronchitis, hemosiderosis, immunologic interstitial fibrosis, immuno adenocarcinoma, adenoid cystic carcinoma, adenosquamous logic interstitial pneumonitis, immunologic lung disease, carcinoma, adenovirus, adult respiratory distress syndrome infections causing chronic granulomatous inflammation, (shock lung), agenesis, AIDS, air embolism, allergic bron infections causing chronic Suppurative inflammation, infec chopulmonary mycosis, allergic granulomatosis and angiitis tions of the air passages, infiltrative lung disease, inflam (Churg-Strauss), allograft rejection, aluminum pneumoco matory lesions, inflammatory pseudotumors, influenza, niosis, alveolar microlithiasis, alveolar proteinosis, amebic interstitial diseases of uncertain etiology, interstitial lung lung abscess, amniotic fluid embolism, amyloidosis of the disease, interstitial pneumonitis in connective tissue dis lung, anomalies of pulmonary vasculature, anomalous pull eases, intralobar sequestration of the lung (congenital), monary venous return, apiration pneumonia, aplasia, asbes intrinsic (nonallergic) asthma, invasive pulmonary tosis, asbestos-related diseases, aspergillosis, asthma, aspergillosis, kaolin pneumoconiosis, Kartagner's Syn atelectasis, atriovenous fistulas, atypical mycobacterial drome, Klebsiella pneumonia, Langerhans cell histiocytosis infection, bacteremia, bacterial pneumonia, benign clear cell (histiocytosis X), large cell undifferentiated carcinoma, lar tumor, benign epithelial tumors, benign fibrous mesothe Val migration of Ascaris lumbricoides, larval migration of lioma, berylliosis, blastomycosis, bromchial atresia, bron Strongyloides Stercoralis, left pulmonary artery 'sling'. chial asthma, bronichial carcinoid tumor, bronchial isomer Legionella pneumonia, lipid pneumonia, lobar pneumonia, ism, bronchial obstruction, bronchial Stenosis, localized emphysema, long-standing bronchial obstruction, bronchiectasis, bronchiolalveolar carcinoma, bronchiolitis, lung abscess, lung collapse, lung fluke, lung transplantation bronchiolitis obliterans-organizing pneumonia, bronchocen implantation response, lymphangiomyomatosis, lympho tric granulomatosis, bronchogenic cyst, bronchopneumonia, cytic interstitial pneumonitis (pseudolymphoma, lymphoma, bronchopulmonary dysplasia, bronchopulmonary sequestra lymphomatoid granulomatosis, malignant mesothelioma, tion, bullae, bullous emphysema, cancer, carcinoid tumors, massive pulmonary hemorrhage in the newborn, measles, carcinoma of the lung (bronchogenic carcinoma), central meconium aspiration syndrome, mesenchymal cystic hama (bronchogenic) carcinoma, central cyanosis, centriacinar rtomas, mesenchymal tumors, mesothelioma, metal-induced emphysema, cetrilobular emphysema, chest pain, Chlamy lung diseases, metastatic calcification, metastatic neo dial pneumonia, chondroid hamartoma, chronic airflow plasms, metastatic ossification, mica pneumoconiosis, obstruction, chronic bronchitis, chronic diffuse interstitial mixed dust fibrosis, mixed epithelial-mesenchymal tumors, lung disease, chronic idiopathic pulmonary fibrosis, chronic mixed type neoplasms, mucoepidermoid tumor, mucovisci lung abscess, chronic obstructive pulmonary diseases, dosis (fibrocystic disease of the pancreas), mycoplasma chronic radiation pneumonitis, chronic silicosis, chylotho pneumoniae, necrotizing bacterial pneumonia, necrotizing rax, ciliary dyskinesia, coal worker's pneumoconiosis sarcoid granulomatosis, neonatal respiratory distress Syn (anthracosis), coccidioidomycosis, collagen-vascular dis drome, neoplasms of the pleura, neuromuscular syndromes, eases, common cold, compensatory emphysema, congenital nocardiosis, nondestructive lung disease, North American acinar dysplasia, congenital alveolar capillary dysplasia, blastomycosis, occupational asthma, organic dust disease, congenital bronchobiliary fistula, congenital bronchoesoph panacinar emphysema, Pancoast's syndrome, paracoccidio ageal fistula, congenital cystic adenomatoid malformation, idomycosis, parainfluenza, paraneoplastic syndromes, congenital pulmonary lymphangiectasis, congenital pulmo paraseptal emphysema (paracicatricial), parasilicosis Syn nary overinflation (congenital emphysema), congestion, dromes, parasitic infections of the lung, peripheral cyanosis, cough, cryptococcosis, cyanosis, cystic fibrosis, cysticerco peripheral lung carcinoma, persistent pulmonary hyperten sis, cytomegalovirus, descquamative interstitial pneumonitis, sion of the newborn, pleural diseases, pleural effusion, destructive lung disease, diatomaceous earth pneumoconio pleural plaques, pneumococcal pneumonia, pneumoconi sis, diffuse alveolar damage, diffuse pulmonary hemorrhage, oses (inorganic dust diseases), Pneumocystis carinii pneu diffuse septal amyloidosis, difuse panbronchiolitis, Dirofi monia, pneumocystosis, pneumonitis, pneumothorax, pre laria immitis, diseases of the pleura, distal acinar (paracep capillary pulmonary hypertension, primary (childhood) US 2006/0134109 A1 Jun. 22, 2006 tuberculosis, primary (idiopathic) pulmonary hypertension, administering to an animal (e.g., a human) a compound that primary mesothelial neoplasms, primary pulmonary hyper modulates the biological activity of a GPCR polypeptide tensions, progressive massive fibrosis, psittacosis, pulmo substantially identical to a polypeptide listed in Tables 22 nary actinomycosis, pulmonary air-leak syndromes, pulmo and 33. nary alveolar proteinosis, pulmonary arteriovenous malformation, pulmonary blastoma, pulmonary capillary 0153. In yet another aspect, the invention features a hemangiomatosis, pulmonary carcinosarcoma, pulmonary method for determining whether a candidate compound is a edema, pulmonary embolism, pulmonary eosinophilia, pull compound that may be useful for the treatment of a muscular monary fibrosis, pulmonary hypertension, pulmonary hypo disease or disorder. This method includes the steps of (a) plasia, pulmonary infarction, pulmonary infiltration and providing a GPCR polypeptide substantially identical to a eosinophilia, pulmonary interstitial air (pulmonary intersti polypeptide listed in Tables 22 and 33; (b) contacting the tial emphysema), pulmonary lesions, pulmonary nocardio GPCR polypeptide with the candidate compound; and (c) sis, pulmonary parenchymal anomalies, pulmonary throm measuring biological activity of the GPCR polypeptide, boembolism, pulmonary tuberculosis, pulmonary vascular wherein altered biological activity, relative to that of the disorders, pulmonary vasculitides, pulmonary veno-occlu GPCR polypeptide not contacted with the compound, indi sive disease, pyothorax, radiation pneumonitis, recurrent cates that the candidate compound may be useful for the pulmonary emboli, red hepatization, respiration failure, res treatment of a muscular disease or disorder. The GPCR piratory syncytial virus, Reye's syndrome, rheumatoid lung polypeptide can be in a cell or in a cell-free assay system. disease, Rickettsial pneumonia, rupture of pulmonary arter 0154) In yet another aspect, the invention features a ies, sarcoidosis, Scar cancer, Scimitar syndrome, Sclero method for determining whether a candidate compound is a derma, Sclerosing hemangioma, secondary (adult) tubercu compound that may be useful for the treatment of a muscular losis, secondary bacterial pneumonia, secondary pleural disease or disorder. This method includes the steps of (a) neoplasms, secondary pulmonary hypertension, senile providing a transgenic non-human mammal (e.g., a knock emphysema, siderosis, silicate pneumoconiosis asbestosis, out mouse) having a disruption in a nucleic acid molecule silicatosis, silicosis, simple nodular silicosis, Sjögren's Syn encoding a GPCR polypeptide substantially identical to a drome, Small airway lesions, Small cell carcinoma, Small cell polypeptide listed in Tables 22 and 33; (b) contacting the undifferentiated (oat cell) carcinoma, spontaneous pneu transgenic non-human mammal with the candidate com mothorax, sporotrichosis, sputum production, Squamous pound; and (c) measuring biological activity of the GPCR (epidermoid) carcinoma, Stannosis, Staphlococcal pneumo polypeptide in the transgenic non-human mammal, wherein nia, Suppuration (abscess formation), Systemic lupus erythe altered biological activity, relative to that of the transgenic matosus, talcosis, tension pneumothorax, tracheal agenesis, non-human mammal not contacted with the compound, tracheal Stenosis, tracheobronchial amyloidosis, tracheo indicates that the candidate compound may be useful for the bronchomegaly, tracheoesophageal fistula, transient tachyp treatment of a muscular disease or disorder. nea of the newborn (neonatal wet lung), tungsten carbide pneumoconiosis, usual interstitial pneumonia, usual inter 0.155. In yet another aspect, the invention features a Stitial pneumonitis, varicella, viral pneumonia, visceral pleu method for determining whether a candidate compound is a ral thickening, Wegener's granulomatosis, and whooping compound that may be useful for the treatment of a muscular disease or disorder. This method includes the steps of (a) cough (pertussis). providing a transgenic non-human mammal (e.g., a mouse) 0147 In another aspect, the invention features a non overexpressing a nucleic acid molecule encoding a GPCR human mammal (e.g., a mouse), having a transgene that polypeptide Substantially identical to a polypeptide listed in includes a nucleic acid molecule encoding a GPCR polypep Tables 22 and 33; (b) contacting the transgenic non-human tide substantially identical to a polypeptide listed in Table mammal with the candidate compound; and (c) measuring 21. biological activity of the GPCR polypeptide in the trans 0148. In yet another aspect, the invention features a genic non-human mammal, wherein altered biological activ non-human mammal (e.g., a mouse), having a mutation in a ity, relative to that of the transgenic non-human mammal not nucleic acid molecule encoding a GPCR polypeptide sub contacted with the compound, indicates that the candidate stantially identical to a polypeptide listed in Table 21. compound may be useful for the treatment of a muscular 0149. In a related aspect, the invention features a cell disease or disorder. from a non-human mammal having a transgene that includes 0.156. In still another aspect, the invention features a nucleic acid molecule encoding a GPCR polypeptide another method for determining whether a candidate com substantially identical to a polypeptide listed in Table 21. pound may be useful for the treatment of a muscular disease 0150. In another aspect, the invention features a cell from or disorder. This method includes (a) providing a nucleic a non-human mammal having a mutation in a nucleic acid acid molecule comprising a promoter from a gene encoding molecule encoding a GPCR polypeptide substantially iden a GPCR polypeptide listed in Tables 22 and 33, the promoter tical to a polypeptide listed in Table 21. operably linked to a reporter system; (b) contacting the 0151. In another aspect, the invention features a method nucleic acid molecule with the candidate compound; and (c) of preventing or treating muscular disease, including intro measuring reporter activity, wherein altered reporter activity, ducing into a human an expression vector that includes a relative to a nucleic acid molecule not contacted with the nucleic acid molecule encoding a GPCR polypeptide sub compound, indicates that the candidate compound may be stantially identical to a polypeptide listed in Tables 22 and useful for the treatment of a muscular disease or disorder. 33, operably linked to a promoter. 0157. In another aspect, the invention features yet 0152. In still another aspect, the invention features a another method for determining whether a candidate com method of treating or preventing muscular disease, including pound may be useful for the treatment of a muscular disease US 2006/0134109 A1 Jun. 22, 2006 20 or disorder. This method includes the steps of: (a) providing candidate therapeutic compounds may be identified include a GPCR polypeptide substantially identical to a polypeptide abnormalities of ion channel closure, acetylcholine receptor listed in Tables 22 and 33; (b) contacting the polypeptide deficiency, acetylcholinesterase deficiency, acid maltase with the candidate compound; and (c) measuring interaction deficiencies (type 2 glycogenosis), acquired myopathies, of the candidate compound to the polypeptide. Interaction of acquired myotonia, adult myotonic dystrophy, alveolar rhab the compound to the polypeptide indicates that the candidate domyosarcoma, aminoglycoside drugs, amyloidosis, amyo compound may be useful for the treatment of a muscular trophic lateral Sclerosis, antimyelin antibodies, bacteremic disease or disorder. myositis, Batten's disease (neuronal ceroid lipofuscinoses), 0158. In still another aspect, the invention features Becker's muscular dystrophy, benign neoplasms, Bornholm another method for determining whether a candidate com disease, botulism, branching enzyme deficiency (type 4 pound may be useful for the treatment of a muscular disease glycogenosis), carbohydrate storage diseases, camitine defi or disorder. This method includes (a) providing a GPCR ciencies, camitine palmitoyltransferase deficiency, central polypeptide Substantially identical to a polypeptide listed in core disease, centronuclear (myotubular) myopathy, Cha Tables 22 and 33; (b) contacting the polypeptide with the gas disease, chondrodystrophic myotonia, chronic renal candidate compound; and (c) measuring the half-life of the disease, congenital fiber type disproportion, congenital mus polypeptide, wherein an alteration in the half-life of the cular dystrophy, congenital myopathies, congenital myo polypeptide, relative to that of the polypeptide not contacted tonic dystrophy, congenital paucity of synaptic clefts, cys with the compound, indicates that the candidate compound ticercosis, cytoplasmic body myopathy, debranching may be useful for the treatment of a muscular disease or disorder. Preferably the GPCR polypeptide is in a cell or a enzyme deficiency (type 3 glycogenosis), defect in acetyl cell free assay system. choline synthesis, denervation, dermatomyositis, diabetes mellitus, diphtheria, disorders of glycolysis, disorders of 0159. In another aspect, the invention features a method neuromuscular junction, distal muscular dystrophy, drug for determining whether a patient has an increased risk for induced inflammatory myopathy, Duchenne muscular dys developing a muscular disease or disorder. The method trophy, embryonal rhabdomyosarcoma, Emery-Dreifuss includes the step of determining whether the patient has a muscular dystrophy, exotoxic bacterial infections, facios mutation in a gene encoding a polypeptide listed in Tables capulohumeral muscular dystrophy, failure of neuromuscu 22 and 33, wherein presence of the mutation indicates that lar transmission, fiber necrosis, fibromyalgia, fingerprint the patient may have an increased risk for developing a body myopathy, Forbe's disease, gas gangrene, Guillain muscular disease or disorder. Barre Syndrome, inclusion body myositis, infantile spinal 0160 In a related aspect, the invention features another muscular atrophies, infectious myositis, inflammatory myo method for determining whether a patient has an increased pathies, influenza, Isaac's syndrome, ischemia, Keams risk for developing a muscular disease or disorder. This Sayre syndrome, lactase dehydrogenase deficiency, Lam method includes the step of determining whether the patient bert-Eaton syndrome, Leigh's disease, leuknock has a polymorphism in a gene encoding a polypeptide listed outdystrophies, limb girdle muscular dystrophy, lipid stor in Tables 22 and 33, wherein presence of the polymorphism age myopathies, Luft's disease, lysosomal glycogen storage indicates that the patient may have an increased risk for disease with normal acid maltase activity, maignant neo developing a muscular disease or disorder. plasms, malignant hyperthermia, McArdle's disease, 0161 In either of these two methods, the mutation or MELAS syndrome (mitochondrial myopathy, encephalopa polymorphism is preferably associated with an alteration thylacticacidosis, and strokes), MERRF syndrome (myo (for example, a decrease) in the biological activity of the clonus epilepsy with ragged-red fibers), metabolic myopa polypeptide. thies, microfiber myopathy, mitochondrial myopathies, 0162. In another aspect, the invention features another multicore disease (minicore disease), multisystem triglycer method for determining whether a patient has an increased ide storage disease, muscle wasting from diabetes, muscular risk for developing a muscular disease or disorder. The dystrophies, myasthenia gravis, myasthenic syndrome method includes measuring biological activity of a GPCR (Eaton-Lambert syndrome), myoadenylate deaminase defi polypeptide from the patient that is substantially identical to ciency, myoglobinuria, myopathies, myophosphorylase a polypeptide listed in Tables 22 and 33, wherein increased deficiency (type 5 glycogenosis), myositis, myositis ossifi or decreased levels in the GPCR biological activity, relative cans, myotonia congenita, myotonic muscular dystrophy, nemaline myopathy, ocular muscular dystrophy, oculopha to normal levels, indicate that the patient may have an ryngeal muscular dystrophy, paramyotonia, parasytic myo increased risk for developing a muscular disease or disorder. pathies, periodic paralysis, peripheral neuropathies, phos 0163. In still another aspect, the invention features yet phofructokinase deficiency (type 7 glycogenosis), another method for determining whether a patient has an phosphoglycerate kinase deficiency, phosphoglycerate increased risk for developing a muscular disease or disorder. mutase deficiency, pleomorphic rhabdomyosarcoma, poly The method includes the step of measuring the patients myositis, Pompe's disease, progressive muscular atrophy, expression levels of a polypeptide listed in Tables 22 and 33, progressive systemic sclerosis, reducing body myopathy, wherein altered levels in the expression, relative to normal, RefSum's disease, rhabdomyolysis, rhabdomyoma, rhab indicate that the patient has an increased risk for developing domyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubu a muscular disease or disorder. Preferably, the expression lar myopathy, secondary congenital myopathies, slow chan levels are determined by measuring levels of polypeptide or nel syndrome, spasmodic torticollis, spheroid body mRNA. myopathy, spinal muscular atrophy, Steroid myopathy, stiff 0164 Preferred muscular diseases that can be treated or person syndrome, systemic lupus erythematosus, Tauri's diagnosed using the methods of the invention or for which disease, tick paralysis, toxic myopathies, toxoplasmosis, US 2006/0134109 A1 Jun. 22, 2006 trichinosis, trilaminar fiber myopathy, type 2 myofiberatro 0.173) In yet another aspect, the invention features a phy, typhoid fever, Vasculitis, viral myositis, and Zebra body method for determining whether a candidate compound is a myopathy. compound that may be useful for the treatment of a disease or disorder of the ovary. This method includes the steps of 0165. In another aspect, the invention features a non (a) providing a transgenic non-human mammal (e.g., a human mammal (e.g., a mouse), having a transgene that mouse) overexpressing a nucleic acid molecule encoding a includes a nucleic acid molecule encoding a GPCR polypep GPCR polypeptide substantially identical to a polypeptide tide substantially identical to a polypeptide listed in Table listed in Tables 23 and 33; (b) contacting the transgenic 22. non-human mammal with the candidate compound; and (c) 0166 In yet another aspect, the invention features a measuring biological activity of the GPCR polypeptide in non-human mammal (e.g., a mouse), having a mutation in a the transgenic non-human mammal, wherein altered biologi nucleic acid molecule encoding a GPCR polypeptide sub cal activity, relative to that of the transgenic non-human stantially identical to a polypeptide listed in Table 22. mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a 0167. In a related aspect, the invention features a cell disease or disorder of the ovary. from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a GPCR polypeptide 0.174. In still another aspect, the invention features substantially identical to a polypeptide listed in Table 22. another method for determining whether a candidate com pound may be useful for the treatment of a disease or 0168 In another aspect, the invention features a cell from disorder of the ovary. This method includes (a) providing a a non-human mammal having a mutation in a nucleic acid nucleic acid molecule comprising a promoter from a gene molecule encoding a GPCR polypeptide substantially iden encoding a GPCR polypeptide listed in Tables 23 and 33, the tical to a polypeptide listed in Table 22. promoter operably linked to a reporter system; (b) contact 0169. In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the ovary including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 23 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the ovary. 0170 In still another aspect, the invention features a 0.175. In another aspect, the invention features yet method of treating or preventing a disease of the ovary another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the ovary. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (b) contacting the Tables 23 and 33. polypeptide with the candidate compound; and (c) measur 0171 In yet another aspect, the invention features a ing interaction of the candidate compound to the polypep method for determining whether a candidate compound is a tide. Interaction of the compound to the polypeptide indi compound that may be useful for the treatment of a disease cates that the candidate compound may be useful for the or disorder of the ovary. This method includes the steps of treatment of a disease or disorder of the ovary. (a) providing a GPCR polypeptide substantially identical to 0176). In still another aspect, the invention features a polypeptide listed in Tables 23 and 33; (b) contacting the another method for determining whether a candidate com GPCR polypeptide with the candidate compound; and (c) pound may be useful for the treatment of a disease or measuring biological activity of the GPCR polypeptide, disorder of the ovary. This method includes (a) providing a wherein altered biological activity, relative to that of the GPCR polypeptide substantially identical to a polypeptide GPCR polypeptide not contacted with the compound, indi listed in Tables 23 and 33; (b) contacting the polypeptide cates that the candidate compound may be useful for the with the candidate compound; and (c) measuring the half treatment of a disease or disorder of the ovary. The GPCR life of the polypeptide, wherein an alteration in the half-life polypeptide can be in a cell or in a cell-free assay system. of the polypeptide, relative to that of the polypeptide not 0172 In yet another aspect, the invention features a contacted with the compound, indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of disease or disorder of the ovary. Preferably the GPCR polypeptide is in disorder of the ovary. This method includes the steps of (a) a cell or a cell free assay system. providing a transgenic non-human mammal (e.g., a knock out mouse) having a disruption in a nucleic acid molecule 0177. In another aspect, the invention features a method encoding a GPCR polypeptide substantially identical to a for determining whether a patient has an increased risk for polypeptide listed in Tables 23 and 33; (b) contacting the developing a disease or disorder of the ovary. The method transgenic non-human mammal with the candidate com includes the step of determining whether the patient has a pound; and (c) measuring biological activity of the GPCR mutation in a gene encoding a polypeptide listed in Tables polypeptide in the-transgenic non-human mammal, wherein 23 and 33, wherein presence of the mutation indicates that altered biological activity, relative to that of the transgenic the patient may have an increased risk for developing a non-human mammal not contacted with the compound, disease or disorder of the ovary. indicates that the candidate compound may be useful for the 0.178 In a related aspect, the invention features another treatment of a disease or disorder of the ovary. method for determining whether a patient has an increased US 2006/0134109 A1 Jun. 22, 2006 22 risk for developing a disease or disorder of the ovary. This 0185. In a related aspect, the invention features a cell method includes the step of determining whether the patient from a non-human mammal having a transgene that includes has a polymorphism in a gene encoding a polypeptide listed a nucleic acid molecule encoding a GPCR polypeptide in Tables 23 and 33, wherein presence of the polymorphism substantially identical to a polypeptide listed in Table 23. indicates that the patient may have an increased risk for 0186. In another aspect, the invention features a cell from developing a disease or disorder of the ovary. a non-human mammal having a mutation in a nucleic acid 0179. In either of these two methods, the mutation or molecule encoding a GPCR polypeptide substantially iden polymorphism is preferably associated with an alteration tical to a polypeptide listed in Table 23. (for example, a decrease) in the biological activity of the 0187. In another aspect, the invention features a method polypeptide. of preventing or treating blood disease, including introduc ing into a human an expression vector that includes a nucleic 0180. In another aspect, the invention features another acid molecule encoding a GPCR polypeptide substantially method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. The identical to a polypeptide listed in Tables 24 and 33, oper method includes measuring biological activity of a GPCR ably linked to a promoter. polypeptide from the patient that is substantially identical to 0188 In still another aspect, the invention features a a polypeptide listed in Tables 23 and 33, wherein increased method of treating or preventing blood disease, including or decreased levels in the GPCR-biological activity, relative administering to an animal (e.g., a human) a compound that to normal levels, indicate that the patient may have an modulates the biological activity of a GPCR polypeptide increased risk for developing a disease or disorder of the substantially identical to a polypeptide listed in Tables 24 ovary. and 33. 0189 In yet another aspect, the invention features a 0181. In still another aspect, the invention features yet method for determining whether a candidate compound is a another method for determining whether a patient has an compound that may be useful for the treatment of a blood increased risk for developing a disease or disorder of the disease or disorder. This method includes the steps of (a) ovary. The method includes the step of measuring the providing a GPCR polypeptide substantially identical to a patient’s expression levels of a polypeptide listed in Tables polypeptide listed in Tables 24 and 33; (b) contacting the 23 and 33, wherein altered levels in the expression, relative GPCR polypeptide with the candidate compound; and (c) to normal, indicate that the patient has an increased risk for measuring biological activity of the GPCR polypeptide, developing a disease or disorder of the ovary. Preferably, the wherein altered biological activity, relative to that of the expression levels are determined by measuring levels of GPCR polypeptide not contacted with the compound, indi polypeptide or mRNA. cates that the candidate compound may be useful for the 0182 Diseases of the ovary that can be treated or diag treatment of a blood disease or disorder. The GPCR nosed using the methods of the invention or for which polypeptide can be in a cell or in a cell-free assay system. candidate therapeutic compounds may be identified include 0190. In yet another aspect, the invention features a autoimmune oophoritis, brenner tumors, choriocarcinoma, method for determining whether a candidate compound is a clear cell adenocarcinoma, clear cell carcinoma, corpus compound that may be useful for the treatment of a blood luteal cysts, decidual reaction, dysgerminoma, embryonal disease or disorder. This method includes the steps of (a) carcinoma, endometrioid tumors, endometriosis, endometri providing a transgenic non-human mammal (e.g., a knock otic cysts, epithelial inclusion cysts, fibrothecoma, follicular out mouse) having a disruption in a nucleic acid molecule cysts, gonadoblastoma, granulosa-stroma cell tumors, encoding a GPCR polypeptide substantially identical to a granulosa-theca cell tumor, gynandroblastoma, hilum cell polypeptide listed in Tables 24 and 33; (b) contacting the hyperplasia, luteal cysts, luteal hematomas, luteoma of transgenic non-human mammal with the candidate com pregnancy, massive ovarian edema, metastatic neoplasm, pound; and (c) measuring biological activity of the GPCR mixed germ cell tumors, monodermal tumors, mucinous polypeptide in the transgenic non-human mammal, wherein tumors, neoplastic cysts, ovarian changes secondary to cyto altered biological activity, relative to that of the transgenic toxic drugs and radiation, ovarian fibroma, polycystic ovary non-human mammal not contacted with the compound, syndrome, pregnancy luteoma, premature follicle depletion, indicates that the candidate compound may be useful for the pseudomyxoma peritonei, resistant ovary, serous tumors, treatment of a blood disease or disorder. Sertoli-Leydig cell tumor, sex-cord tumor with annular 0191 In yet another aspect, the invention features a tubules, Steroid (lipid) cell tumor, Stromal hyperplasia, stro method for determining whether a candidate compound is a mal hyperthecosis, teratoma, theca lutein cysts, thecomas, compound that may be useful for the treatment of a blood transitional cell carcinoma, undifferentiated carcinoma, and disease or disorder. This method includes the steps of (a) yolk sac carcinoma (endodermal sinus tumor). providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a GPCR 0183 In another aspect, the invention features a non polypeptide Substantially identical to a polypeptide listed in human mammal (e.g., a mouse), having a transgene that Tables 24 and 33; (b) contacting the transgenic non-human includes a nucleic acid molecule encoding a GPCR polypep mammal with the candidate compound; and (c) measuring tide substantially identical to a polypeptide listed in Table biological activity of the GPCR polypeptide in the trans 23. genic non-human mammal, wherein altered biological activ 0184 In yet another aspect, the invention features a ity, relative to that of the transgenic non-human mammal not non-human mammal (e.g., a mouse), having a mutation in a contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a blood disease stantially identical to a polypeptide listed in Table 23. or disorder. US 2006/0134109 A1 Jun. 22, 2006

0192 In still another aspect, the invention features polypeptide listed in Tables 24 and 33, wherein increased or another method for determining whether a candidate com decreased levels in the GPCR biological activity, relative to pound may be useful for the treatment of a blood disease or normal levels, indicate that the patient may have an disorder. This method includes (a) providing a nucleic acid increased risk for developing a blood disease or disorder. molecule comprising a promoter from a gene encoding a 0199. In still another aspect, the invention features yet GPCR polypeptide listed in Tables 24 and 33, the promoter another method for determining whether a patient has an operably linked to a reporter system; (b) contacting the increased risk for developing a blood disease or disorder. nucleic acid molecule with the candidate compound; and (c) The method includes the step of measuring the patients measuring reporter activity, wherein altered reporter activity, expression levels of a polypeptide listed in Tables 24 and 33, relative to a nucleic acid molecule not contacted with the wherein altered levels in the expression, relative to normal, compound, indicates that the candidate compound may be indicate that the patient has an increased risk for developing useful for the treatment of a blood disease or disorder. a blood disease or disorder. Preferably, the expression levels 0193 In another aspect, the invention features yet are determined by measuring levels of polypeptide or another method for determining whether a candidate com mRNA. pound may be useful for the treatment of a blood disease or 0200 Preferred blood diseases that can be treated or disorder. This method includes the steps of: (a) providing a diagnosed using the methods of the invention or for which GPCR polypeptide substantially identical to a polypeptide candidate therapeutic compounds may be identified include listed in Tables 24 and 33; (b) contacting the polypeptide abnormal hemoglobins, abnormalities in granulocyte count, with the candidate compound; and (c) measuring interaction abnormalities in lymphocyte count, abnormalities in mono of the candidate compound to the polypeptide. Interaction of cyte count, abnormalities of blood platelets, abnormalitites the compound to the polypeptide indicates that the candidate of platelet function, acanthocytosis, acquired neutropenia, compound may be useful for the treatment of a blood disease acute granulocytic leukemia, acute idiopathic thrombocy or disorder. topenic purpura, acute infections, acute lymphoblastic leu kemia, acute lymphocytic leukemia, acute myeloblastic leu 0194 In still another aspect, the invention features kemia, acute myelocytic leukemia, acute myeloid leukemia, another method for determining whether a candidate com acute pyogenic bacterial infections, acute red cell aplasia, pound may be useful for the treatment of a blood disease or acute response to endotoxin, adult T-cell leukemial/lym disorder. This method includes (a) providing a GPCR phoma, afibrinogenemia, alpha thalassemia, altered affinity polypeptide substantially identical to a polypeptide listed in of hemoglobin for oxygen, amyloidosis, anemia, anemia due Tables 24 and 33; (b) contacting the polypeptide with the to acute blood loss, anemia due to chronic blood loss, candidate compound; and (c) measuring the half-life of the anemia of chronic disease, anemia of chronic renal failure, polypeptide, wherein an alteration in the half-life of the anemias associated with enzyme deficiencies, anemias asso polypeptide, relative to that of the polypeptide not contacted ciated with erythrocyte cytoskeletal defects, anemias caused with the compound, indicates that the candidate compound by inherited disorders of hemoglobin Synthesis, angiogenic may be useful for the treatment of a blood disease or myeloid metaplasia, aplastic anemia, ataxia-ielangiectasia, disorder. Preferably the GPCR polypeptide is in a cell or a Auer rods, autoimmune hemolytic anemias, B-cell chronic cell free assay system. lymphocytic leukemia, B-cell chronic lymphoproliferative 0.195. In another aspect, the invention features a method disorders, Bernard-Soulier disease, beta thalassemia, Black for determining whether a patient has an increased risk for fan-Diamond disease, brucellosis, Burkitt's lymphoma, developing a blood disease or disorder. The method includes Chédiak-Higashi syndrome, cholera, chronic acquired pure the step of determining whether the patient has a mutation in red cell aplasia, chronic granulocytic leukemia, chronic a gene encoding a polypeptide listed in Tables 24 and 33. granulomatous disease, chronic idiopathic myelofibrosis, wherein presence of the mutation indicates that the patient chronic idiopathic thrombocytopenic purpura, chronic lym may have an increased risk for developing a blood disease phocytic leukemia, chronic lymphoproliferative disorders, or disorder. chronic myelocytic leukemia, chronic myelogenous leuke mia, chronic myeloid leukemia, chronic myeloproliferative 0196. In a related aspect, the invention features another disorders, congenital dyserythropoietic anemias, congenital method for determining whether a patient has an increased dysfibrinogenemia, congenital neutropenia, corticosteriods, risk for developing a blood disease or disorder. This method cyclic neutropenia, cytoplasmic maturation defect, defi includes the step of determining whether the patient has a ciency of coagulation factors, delta-beta thalassemia, diph polymorphism in a gene encoding a polypeptide listed in theria, disorders of blood coagulation, disseminated intra Tables 24 and 33, wherein presence of the polymorphism vascular coagulation & fibrinolysis, Döhle bodies, drug & indicates that the patient may have an increased risk for chemical-induced hemolysis, drug-induced thrombocytope developing a blood disease or disorder. nia, drugs that Suppress granulopoiesis, E. coli, early preleu 0197). In either of these two methods, the mutation or kemic myeloid leukemia, eosinophilia, eosinophilic granu polymorphism is preferably associated with an alteration loma, erythrocute enzyme deficiency, erythrocyte membrane (for example, a decrease) in the biological activity of the defects, essential thrombocythemia, factor 7 deficiency, polypeptide. familial cyclic neutropenia, Felty’s syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher 0198 In another aspect, the invention features another disease, Glanzmann's thrombasthenia, glucose-6-phosphate method for determining whether a patient has an increased dehydrogenase deficiency, granulated T-cell lymphocyte risk for developing a blood disease or disorder. The method leukemia, granulocytic sarcoma, granulocytosis, Hageman includes measuring biological activity of a GPCR polypep trait, hairy cell leukemia (leukemic reticuloendotheliosis), tide from the patient that is substantially identical to a Hand-Schüller-Christian disease, heavy-chain disease, US 2006/0134109 A1 Jun. 22, 2006 24 hemoglobin C disease, hemoglobin constant spring, hemo 0202) In yet another aspect, the invention features a globin S, hemoglobinopathies, hemolysis caused by infec non-human mammal (e.g., a mouse), having a mutation in a tious agents, hemolytic anemia, hemolytic anemia second nucleic acid molecule encoding a GPCR polypeptide sub ary to mechanical erythrocyte destruction, hemolytic blood stantially identical to a polypeptide listed in Table 24. transfusion reactions, hemolytic disease of the newborn, 0203. In a related aspect, the invention features a cell hemophagocytic disorders, hemophilia A, hemophilia B from a non-human mammal having a transgene that includes (Christmas disease, factor 9 deficiency, hepatitis, hereditary a nucleic acid molecule encoding a GPCR polypeptide elliptocytosis, hereditary spherocytosis, heterozygous beta substantially identical to a polypeptide listed in Table 24. thalassemia (Cooley's trait), homozygous beta thalassemia (Cooley's anemia), hypereosinophilic syndrome, hypoxia, 0204. In another aspect, the invention features a cell from idiopathic cold hemagglutinin disease, idiopathic thromb a non-human mammal having a mutation in a nucleic acid ocytopenic purpura, idiopathic warm autoimmune molecule encoding a GPCR polypeptide substantially iden hemolytic anemia, immune drug induced hemolysis, tical to a polypeptide listed in Table 24. immune-mediated hemolytic anemias, immunodeficiency 0205. In another aspect, the invention features a method disease, infantile neutropenia (Knockoutstmann), instability of preventing or treating a disease of the prostate including of the hemoglobin molecule, iron deficiency anemia, iso introducing into a human an expression vector that includes immune hemolytic anemia, juvenile chronic myeloid leuke a nucleic acid molecule encoding a GPCR polypeptide mia, Langerhans cell histiocytosis, large granular lympho substantially identical to a polypeptide listed in Tables 25 cyte leukemia, lazy leuknock outcyte syndrome, Letterer and 33, operably linked to a promoter. Siwe disease, leukemias, leukemoid reaction, leuknock 0206. In still another aspect, the invention features a outerythroblastic anemia, lipid storage diseases, lympho method of treating or preventing a disease of the prostate blastosis, lymphocytopenia, lymphocytosis, lymphoma, including administering to an animal (e.g., a human) a lymphopenia, macroangiopathic hemolytic anemia, malaria, compound that modulates the biological activity of a GPCR marrow aplasia, May-Hegglin anomaly, measles, megalo polypeptide Substantially identical to a polypeptide listed in blastic anemia, metabolic diseases, microangiopathic Tables 25 and 33. hemolytic anemia, microcytic anemia, miliary tuberculosis, mixed phenotupe acute leukemia, monoclonal gammopathy 0207. In yet another aspect, the invention features a of undetermined significance, monocytic leukemia, mono method for determining whether a candidate compound is a cytosis, mucopolysaccharidosis, multiple myeloma, myelo compound that may be useful for the treatment of a disease blastic luekemia, myelodysplastic syndromes, myelofibrosis or disorder of the prostate. This method includes the steps of (agnogenic myeloid metaplasia), myeloproliferative dis (a) providing a GPCR polypeptide substantially identical to eases, myelosclerosis, neonatal thrombocytopenic purpura, a polypeptide listed in Tables 25 and 33; (b) contacting the neoplasms of hematopoietic cells, neutropenia, neutrophil GPCR polypeptide with the candidate compound; and (c) dysfunction syndromes, neutrophil leuknock outcytosis, measuring biological activity of the GPCR polypeptide, neutrophilia, Niemann-Pick disease, nonimmune drug-in wherein altered biological activity, relative to that of the duced hemolysis, normocytic anemia, nuclear maturation GPCR polypeptide not contacted with the compound, indi defects, parahemophilia, paroxysmal cold hemoglominuria, cates that the candidate compound may be useful for the paroxysmal nocturnal hemoglobinuria, Pelger-Hijet treatment of a disease or disorder of the prostate. The GPCR anomaly, pernicious (Addisonian) anemia, plasma cell leu polypeptide can be in a cell or in a cell-free assay system. kemia, plasma cell neoplasia, polycythemia, polycythemia 0208. In yet another aspect, the invention features a rubra Vera, presence of circulating anticoagulants, primary method for determining whether a candidate compound is a (idiopathic) thrombocythemia, primary neoplasms, prolym compound that may be useful for the treatment of a disease phocytic leukemia, Proteus, Pseudomonas, pure red cell or disorder of the prostate. This method includes the steps of aplasia, pyogenic bacterial infection, pyruvate kinase defi (a) providing a transgenic non-human mammal (e.g., a ciency, radiation, red cell aplasia, refractory anemias, rick knock-out mouse) having a disruption in a nucleic acid etsial infections, Rosenthal's syndrome, secondary absolute molecule encoding a GPCR polypeptide substantially iden polycythemia, septicemia, severe combined immunodefi tical to a polypeptide listed in Tables 25 and 33; (b) ciency disease, Sézary syndrome, sickle cell disease, sickle contacting the transgenic non-human mammal with the cell-beta thalassemia, sideroblastic anemia, Solitary plasma candidate compound; and (c) measuring biological activity cytoma, storage pool disease, stress, structural hemoglobin of the transgenic non-human mammal, wherein altered bio variants, systemic lupus erythematosus, Systemic mastocy logical activity, relative to that of the transgenic non-human tosis, tart cell, T-cell chronic lymphoproliferative disorders, mammal not contacted with the compound, indicates that the T-cell prolymphocytic leukemia, thalassemias, thrombocy candidate compound may be useful for the treatment of a topenia, thrombotic thrombocytopenic purpura, toxic granu disease or disorder of the prostate. lation, toxic granules in severe infection, typhus, vitamin B12 deficiency, vitamin K deficiency, Von Willebrand’s 0209. In yet another aspect, the invention features a disease, Waldenstrom macroglobulinemia, and Wisknock method for determining whether a candidate compound is a outtt-aldrich syndrome. compound that may be useful for the treatment of a blood disease or disorder of the prostate. This method includes the 0201 In another aspect, the invention features a non steps of (a) providing a transgenic non-human mammal human mammal (e.g., a mouse), having a transgene that (e.g., a mouse) overexpressing a nucleic acid molecule includes a nucleic acid molecule encoding a GPCR polypep encoding a GPCR polypeptide substantially identical to a tide substantially identical to a polypeptide listed in Table polypeptide listed in Tables 25 and 33; (b) contacting the 24. transgenic non-human mammal with the candidate com US 2006/0134109 A1 Jun. 22, 2006 pound; and (c) measuring biological activity of the GPCR 0216) In another aspect, the invention features another polypeptide in the transgenic non-human mammal, wherein method for determining whether a patient has an increased altered biological activity, relative to that of the transgenic risk for developing a disease or disorder of the prostate. The non-human mammal not contacted with the compound, method includes measuring biological activity of a GPCR indicates that the candidate compound may be useful for the polypeptide from the patient that is substantially identical to treatment of a disease or disorder of the prostate. a polypeptide listed in Tables 25 and 33, wherein increased 0210. In still another aspect, the invention features or decreased levels in the GPCR biological activity, relative another method for determining whether a candidate com to normal levels, indicate that the patient may have an pound may be useful for the treatment of a disease or increased risk for developing a disease or disorder of the disorder of the prostate. This method includes (a) providing prostate. a nucleic acid molecule comprising a promoter from a gene 0217. In still another aspect, the invention features yet encoding a GPCR polypeptide listed in Tables 25 and 33, the another method for determining whether a patient has an promoter operably linked to a reporter system; (b) contact increased risk for developing a disease or disorder of the ing the nucleic acid molecule with the candidate compound; prostate. The method includes the step of measuring the and (c) measuring reporter activity, wherein altered reporter patient’s expression levels of a polypeptide listed in Tables activity, relative to a nucleic acid molecule not contacted 25 and 33, wherein altered levels in the expression, relative with the compound, indicates that the candidate compound to normal, indicate that the patient has an increased risk for may be useful for the treatment of a disease or disorder of developing a disease or disorder of the prostate. Preferably, the prostate. the expression levels are determined by measuring levels of 0211. In another aspect, the invention features yet another polypeptide or mRNA. method for determining whether a candidate compound may 0218. Diseases of the prostate that can be treated or be useful for the treatment of a disease or disorder of the diagnosed using the methods of the invention or for which prostate. This method includes the steps of: (a) providing a candidate therapeutic compounds may be identified include GPCR polypeptide substantially identical to a polypeptide acute bacterial prostatitis, acute prostatitis, adenoid basal listed in Tables 25 and 33; (b) contacting the polypeptide cell tumor (adenoid cystic-like tumor), allergic (eosino with the candidate compound; and (c) measuring interaction philic) granulomatous prostatitis, atrophy, atypical of the candidate compound to the polypeptide. Interaction of adenomatous hyperplasia, atypical basal cell hyperplasia, the compound to the polypeptide indicates that the candidate basal cell adenoma, basal cell hyperplasia, BCG-induced compound may be useful for the treatment of a disease or granulomatous prostatitis, benign prostatic hyperplasia, disorder of the prostate. benign prostatic hypertrophy, blue nevus, carcinosarcoma, 0212. In still another aspect, the invention features chronic abacterial prostatitis, chronic bacterial prostatitis, another method for determining whether a candidate com cribrifonn hyperplasia, ductal (endometrioid) adenocarci pound may be useful for the treatment of a disease or noma, granulomatous prostatitis, hematuria, iatrogenic disorder of the prostate. This method includes (a) providing granulomatous prostatitis, idiopathic (nonspecific) granu a GPCR polypeptide substantially identical to a polypeptide lous prostatitis, impotence, infectious granulomatous pros listed in Tables 25 and 33; (b) contacting the polypeptide tatitis, inflammatory pseudotumor, leiomyosarcoma, leuke with the candidate compound; and (c) measuring the half mia, lymphoepithelioma-like carcinoma, malaknock life of the polypeptide, wherein an alteration in the half-life outplakia, malignant lymphoma, mucinous (colloid) carci of the polypeptide, relative to that of the polypeptide not noma, nodular hyperplasia (benign prostatic hyperplasia), contacted with the compound, indicates that the candidate nonbacterial prostatitis, obstruction of urinary outflow, phyl compound may be useful for the treatment of a disease or lodes tumor, postatrophic hyperplasia, postirradiation granu disorder of the prostate. Preferably the GPCR polypeptide is lomatous prostatitis, postoperative spindle cell nodules, in a cell or a cell free assay system. postSurgical granulomatous prostatitis, prostatic adenocar 0213. In another aspect, the invention features a method cinoma, prostatic carcinoma, prostatic intraepithelial neo for determining whether a patient has an increased risk for plasia, prostatic melanosis, prostatic neoplasm, prostatitis, developing a disease or disorder of the prostate. The method rhabdomyosarcoma, sarcomatoid carcinoma of the prostate, includes the step of determining whether the patient has a Sclerosing adenosis, signet ring cell carcinoma, Small-cell, mutation in a gene encoding a polypeptide listed in Tables undifferentiated carcinoma (high-grade neuroendocrine car 25 and 33, wherein presence of the mutation indicates that cinoma), squamous cell carcinoma of the prostate, Stromal the patient may have an increased risk for developing a hyperplasia with atypia, transitional cell carcinoma of the disease or disorder of the prostate. prostate, Xanthogranulomatous prostatitis, and Xanthoma. 0214. In a related aspect, the invention features another 0219. In another aspect, the invention features a non method for determining whether a patient has an increased human mammal (e.g., a mouse), having a transgene that risk for developing a disease or disorder of the prostate. This includes a nucleic acid molecule encoding a GPCR polypep method includes the step of determining whether the patient tide substantially identical to a polypeptide listed in Table has a polymorphism in a gene encoding a polypeptide listed 25. in Tables 25 and 33, wherein presence of the polymorphism indicates that the patient may have an increased risk for 0220. In yet another aspect, the invention features a developing a disease or disorder of the prostate. non-human mammal (e.g., a mouse), having a mutation in a 0215. In either of these two methods, the mutation or nucleic acid molecule encoding a GPCR polypeptide sub polymorphism is preferably associated with an alteration stantially identical to a polypeptide listed in Table 25. (for example, a decrease) in the biological activity of the 0221) In a related aspect, the invention features a cell polypeptide. from a non-human mammal having a transgene that includes US 2006/0134109 A1 Jun. 22, 2006 26 a nucleic acid molecule encoding a GPCR polypeptide 0228. In still another aspect, the invention features substantially identical to a polypeptide listed in Table 25. another method for determining whether a candidate com pound may be useful for the treatment of a skin disease or 0222. In another aspect, the invention features a cell from disorder. This method includes (a) providing a nucleic acid a non-human mammal having a mutation in a nucleic acid molecule comprising a promoter from a gene encoding a molecule encoding a GPCR polypeptide substantially iden GPCR polypeptide listed in Tables 26 and 33.the promoter tical to a polypeptide listed in Table 25. operably linked to a reporter system; (b) contacting the 0223) In another aspect, the invention features a method nucleic acid molecule with the candidate compound; and (c) of preventing or treating skin disease, including introducing measuring reporter activity, wherein altered reporter activity, into a human an expression vector that includes a nucleic relative to a nucleic acid molecule not contacted with the acid molecule encoding a GPCR polypeptide substantially compound, indicates that the candidate compound may be identical to a polypeptide listed in Tables 26 and 33, oper useful for the treatment of a skin disease or disorder. ably linked to a promoter. 0229. In another aspect, the invention features yet 0224. In still another aspect, the invention features a another method for determining whether a candidate com method of treating or preventing skin disease, including pound may be useful for the treatment of a skin disease or administering to an animal (e.g., a human) a compound that disorder. This method includes the steps of: (a) providing a modulates the biological activity of a GPCR polypeptide GPCR polypeptide substantially identical to a polypeptide substantially identical to a polypeptide listed in Tables 26 listed in Tables 26 and 33; (b) contacting the polypeptide and 33. with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of 0225. In yet another aspect, the invention features a the compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a skin disease compound that may be useful for the treatment of a skin or disorder. disease or disorder. This method includes the steps of (a) providing a GPCR polypeptide substantially identical to a 0230. In still another aspect, the invention features polypeptide listed in Tables 26 and 33; (b) contacting the another method for determining whether a candidate com GPCR polypeptide with the candidate compound; and (c) pound may be useful for the treatment of a skin disease or measuring biological activity of the GPCR polypeptide, disorder. This method includes (a) providing a GPCR wherein altered biological activity, relative to that of the polypeptide substantially identical to a polypeptide listed in GPCR polypeptide not contacted with the compound, indi Tables 26 and 33; (b) contacting the polypeptide with the cates that the candidate compound may be useful for the candidate compound; and (c) measuring the half-life of the treatment of a skin disease or disorder. The GPCR polypep polypeptide, wherein an alteration in the half-life of the tide can be in a cell or in a cell-free assay system. polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound 0226. In yet another aspect, the invention features a may be useful for the treatment of a skin disease or disorder. method for determining whether a candidate compound is Preferably the GPCR polypeptide is in a cell or a cell free a-compound that may be useful for the treatment of a skin assay system. disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock 0231. In another aspect, the invention features a method out mouse) having a disruption in a nucleic acid molecule for determining whether a patient has an increased risk for encoding a GPCR polypeptide substantially identical to a developing a skin disease or disorder. The method includes polypeptide listed in Tables 26 and 33; (b) contacting the the step of determining whether the patient has a mutation in transgenic non-human mammal with the candidate com a gene encoding a polypeptide listed in Tables 26 and 33. pound; and (c) measuring biological activity of the GPCR wherein presence of the mutation indicates that the patient polypeptide in the transgenic non-human mammal, wherein may have an increased risk for developing a skin disease or altered biological activity, relative to that of the transgenic disorder. non-human mammal not contacted with the compound, 0232. In a related aspect, the invention features another indicates that the candidate compound may be useful for the method for determining whether a patient has an increased treatment of a skin disease or disorder. risk for developing a skin disease or disorder. This method 0227. In yet another aspect, the invention features a includes the step of determining whether the patient has a method for determining whether a candidate compound is a polymorphism in a gene encoding a polypeptide listed in compound that may be useful for the treatment of a skin Tables 26 and 33, wherein presence of the polymorphism disease or disorder. This method includes the steps of (a) indicates that the patient may have an increased risk for providing a transgenic non-human mammal (e.g., a mouse) developing a skin disease or disorder. overexpressing a nucleic acid molecule encoding a GPCR 0233. In either of these two methods, the mutation or polypeptide Substantially identical to a polypeptide listed in polymorphism is preferably associated with an alteration Tables 26 and 33; (b) contacting the transgenic non-human (for example, a decrease) in the biological activity of the mammal with the candidate compound; and (c) measuring polypeptide. biological activity of the GPCR polypeptide in the trans genic non-human mammal, wherein altered biological activ 0234. In another aspect, the invention features another ity, relative to that of the transgenic non-human mammal not method for determining whether a patient has an increased contacted with the compound, indicates that the candidate risk for developing a skin disease or disorder. The method compound may be useful for the treatment of a disease skin includes measuring biological activity of a GPCR polypep disease or disorder. tide from the patient that is substantially identical to a US 2006/0134109 A1 Jun. 22, 2006 27 polypeptide listed in Tables 26 and 33, wherein increased or nevus, juvenile Xanthogranuloma, Kaposi's sarcoma, kel decreased levels in the GPCR biological activity, relative to oids, keratinocytic lesions;... keratinocytic tumors, keratoa normal levels, indicate that the patient may have an canthoma, keratoderma blennorrhagicum, keratosis pilaris, increased risk for developing a skin disease or disorder. leiomyoma, lentigo, lentigo maligna (Hutchinson's freckle), 0235. In still another aspect, the invention features yet lepromatous leprosy, leprosy (Hansen's disease), leuknock another method for determining whether a patient has an outcytoclastic vasculitis, lichen planus, lichen Sclerosus et increased risk for developing a skin disease or disorder. The atrophicus, lichen simplex chronicus, lichen striatus, method includes the step of measuring the patient’s expres lichenoid disorders, lichenoid drug reactions, light erup sion levels of a polypeptide listed in Tables 26 and 33, tions, linear bullous IgA dermatitis, lipoma, Lucio's phe wherein altered levels in the expression, relative to normal, nomenon, lupus erythematosus, lymphatic filariasis, lym indicate that the patient has an increased risk for developing phocytic vasculitis, lymphocytoma cutis, lymphoid lesions, a skin disease or disorder. Preferably, the expression levels lymphomatoid papulosis, malignant blue nevus, malignant are determined by measuring levels of polypeptide or lymphomas, malignant melanoma, malignant melanoma in mRNA. situ (noninvasive malignant melanoma), mast cell neo 0236 Preferred skin diseases that can be treated or diag plasms, mastocytosis, measles, melanocyte disorders, mel nosed using the methods of the invention or for which anocytic lesions, melanocytic neoplasms, melanocytic candidate therapeutic compounds may be identified include nevus, melanocytic nevus with dysplasia, melanotic macule, acanthosis nigricans, acne Vulgaris, acquired epidermolysis reactive type, melasma, merkel cell (neuroendocrine) carci bullosa, acrochordons, acrodermatitis enteropathica, acro noma, metastatic melanoma, miliara, mixed connective tis pustulosis, actinic keratosis, acute cutaneous lupus erythe Sue disease, molluscum contagiosum, morphea, mucin depo matosus, age spots, allergic dermatitis, alopecia areata, sition, muCOCutaneous leishmaniasis, mycetoma, angioedema, angiokeratoma, angioma, anthrax, apocrine mycobacterial infection, Mycobacterium marinum, Myco tumors, arthropid-bite reactions, atopic dermatitis, atypical bacterium ulcerans, mycosis fungoides (cutaneous T cell fibroXanthoma, Bart's syndrome, basal cell carcinoma (basal lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis cell epithelioma), Bateman's purpura, benign familial pem lipoidica diabeticorum, necrolytic migratory erythema, phigus (Hailey-Hailey disease), benign keratoses, Berloque necrotizing fasciitis, neoplasms of dermal mesenchymal dermatitis, blue nevus, borderline leprosy, Borrelia infection cells, neoplasms of keratinocytes, neoplasms of skin (lyme disease), Bowen's disease (carcinoma in situ), bullous appendages, neoplasms of the epidermis, neural tumors, pemphigoid, Café-au-lait spot, calcification, cellular blue neuroendocrine carcinoma of the skin, neurothekeoma, nevus, cellulitis, Chagas disease, chickenpox (varicella), nevocellular nevus (melanocytic nevus), nummular derma chloasma, chondrodermatitis nodularis helicis, chondroid titis, obliterative vasculitis, onchocerciasis, Paget’s disease, Syringoma, chronic actinic dermatitis, chronic cutaneous pale cell acanthoma of Degos, palisaded encapsulated neu lupus erythematosus, chronic discoid lesions, cicatricial roma, papillomavirus infections, paraneoplastic pemphigus, pemphigoid, collagen abnormalities, compount melanocytic parasitic infections, pemphigoid gestationis, pemphigus, nevus, congenital melanocytic nevus, connective tissue pemphigus foliaceus, pemphigus Vulgaris, perivascular infil nevus, contact dermatitis, cutaneous leishmaniasis, cutis trates, pilar cysts, pinta, pityriasis alba, pityriasis lichenoides laxa, cysts of the skin, dandruff, Darier's disease (keratosis chronica (of Juliusberg), pityriasis lichenoides et variolifor follicularis), deep fungal infections, delayed-hypersensitiv mis acuta, pityriasis rosea, pityriasis rubra pilaris, plantar ity reaction, dermal Spitz's nevus, dermatitis, dermatitis warts, porokeratosis, pressure necrosis, progressive sys herpetiformis, dermatofibroma (cutaneous fibrous histiocy temic sclerosis, protozoal infections, pruritic urticarial pap toma), dermatofibrosarcoma protuberans, dermatomyositis, ules and plasques of pregnancy, pruritisani, pseudofollicu dermatophyte infections, dermatophytid reactions, dermoid litis barbae, pseudoxanthoma elasticum, psoriasis Vulgaris, cyst, dermotropic ricketsial infections, dermotropic viral pyogenic granuloma, radial growild typeh phase melanoma, infections, desmoplastic melanoma, discoid lupus erythema recessive dystrophic epidermolysis bullosa, Reiter's syn tosus, dominant dystrophic epidermolysis bullosa, Dowling drome, ringworm, Rochalimaea hemselae infection, rosacea, Meara epidermolysis bullosa, dyshidrotic dermatitis, dys rubella, Sarcoidosis, Scabies, Schamberg's disease, Sclero plastic nevi, eccrine tumors, ecthyma, eczema, elastic tissue derma, sebaceous hyperplasia, sebaceous tumors, seborrheic abnormalities, elastosis perforans serpiginosa, eosinophilic dermatitis, seborrheic keratosis, Sézary syndrome, skin fasciitis, eosinophilicfolliculitis, ephelides (freckles), epi manifestations of systemic diseases, Small plaque parapso dermal cysts, epidermolysis bullosa, epidermolysis bullosa riasis, Smallpox (variola), Solitary mastocytoma, Spirochetal simplex, epidermotropic T-cell lymphoma, epidermotropic infections, Spitz's nevus, Spitz's nevus junctional type, viruses, erysipelas, erythema multiforme, erythema squamous cell carcinoma, stasis dermatitis, Stevens-Johnson nodosum, erythema nodosum leprosum, fibrotic disorders, syndrome, Subacute cutaneous lupus erythematosus, Subcor fibrous tumors, follicular mucinosis, Fordyce's condition, neal pustular dermatosis, Superficial fungal infections, fungal infections, genodermatoses, graft-versus-host dis Superficial spreading melanoma in situ, Syphilis, Syringoma, ease, granuloma annulare, granulomatous vasculitis, Grov systemic lupus erythematosus, Systemic mastocytosis, tinea er's disease, hair follicle infections, hair follicle tumors, hair (dermatophytosis, tinea versicolor, toxic epidermal necroly loss, halo nevus, herpes simplex, herpes Zoster (shingles), sis, transient acantholytic dermatosis, tuberculoid leprosy, hidradenitis suppurativa, histiocytic lesions, HIV infections, tuberculosis, urticaria, urticaria pigmentosa, urticarial vas hives, human papilloma virus, hyperhydrosis, ichthyosis, culitis, vascular tumors, Verruca Vulgaris (common wart), idiopathic skin diseases, impetigo, incontinentia pigmenti, vertical growild typeh phase melanoma, Visceral leishma intraepidermal spongiotic vesicles and bullae, invasive niasis, vitiligo, warty dyskeratoma, Weber-Cockayne epi malignant melanoma, invasive squamous cell carcinoma, dermolysis bullosa, Woringer-Knock outlopp disease, Xan junctional epidermolysis bullosa, junctional melanocytic thomas, Xeroderma pigmentosum, Xerosis, and yaws. US 2006/0134109 A1 Jun. 22, 2006 28

0237. In another aspect, the invention features a non or disorder of the spleen. This method includes the steps of human mammal (e.g., a mouse), having a transgene that (a) providing a transgenic non-human mammal (e.g., a includes a nucleic acid molecule encoding a GPCR polypep mouse) overexpressing a nucleic acid molecule encoding a tide substantially identical to a polypeptide listed in Table GPCR polypeptide substantially identical to a polypeptide 26. listed in Tables 27 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) 0238. In yet another aspect, the invention features a measuring biological activity of the GPCR polypeptide in non-human mammal (e.g., a mouse), having a mutation in a the transgenic non-human mammal, wherein altered biologi nucleic acid molecule encoding a GPCR polypeptide sub cal activity, relative to that of the transgenic non-human stantially identical to a polypeptide listed in Table 26. mammal not contacted with the compound, indicates that the 0239). In a related aspect, the invention features a cell candidate compound may be useful for the treatment of a from a non-human mammal having a transgene that includes disease disease or disorder of the spleen. a nucleic acid molecule encoding a GPCR polypeptide 0246. In still another aspect, the invention features substantially identical to a polypeptide listed in Table 26. another method for determining whether a candidate com 0240. In another aspect, the invention features a cell from pound may be useful for the treatment of a disease or a non-human mammal having a mutation in a nucleic acid disorder of the spleen. This method includes (a) providing a molecule encoding a GPCR polypeptide substantially iden nucleic acid molecule comprising a promoter from a gene tical to a polypeptide listed in Table 26. encoding a GPCR polypeptide listed in Tables 27 and 33, the promoter operably linked to a reporter system; (b) contact 0241. In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the spleen including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 27 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the spleen. 0242. In still another aspect, the invention features a 0247. In another aspect, the invention features yet method of treating or preventing a disease of the spleen another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the spleen. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a Tables 27 and 33. polypeptide listed in Tables 27 and 33; (b) contacting the 0243 In yet another aspect, the invention features a polypeptide with the candidate compound; and (c) measur method for determining whether a candidate compound is a ing interaction of the candidate compound to the polypep compound that may be useful for the treatment of a disease tide. Interaction of the compound to the polypeptide indi or disorder of the spleen. This method includes the steps of cates that the candidate compound may be useful for the (a) providing a GPCR polypeptide substantially identical to treatment of a disease or disorder of the spleen. a polypeptide listed in Tables 27 and 33; (b) contacting the 0248. In still another aspect, the invention features GPCR polypeptide with the candidate compound; and (c) another method for determining whether a candidate com measuring biological activity of the GPCR polypeptide, pound may be useful for the treatment of a disease or wherein altered biological activity, relative to that of the disorder of the spleen. This method includes (a) providing a GPCR polypeptide not contacted with the compound, indi GPCR polypeptide substantially identical to a polypeptide cates that the candidate compound may be useful for the listed in Tables 27 and 33; (b) contacting the polypeptide treatment of a disease or disorder of the spleen. The GPCR with the candidate compound; and (c) measuring the half polypeptide can be in a cell or in a cell-free assay system. life of the polypeptide, wherein an alteration in the half-life 0244. In yet another aspect, the invention features a of the polypeptide, relative to that of the polypeptide not method for determining whether a candidate compound is a contacted with the compound, indicates that the candidate compound that may be useful for the treatment of a disease compound may be useful for the treatment of a disease or or disorder of the spleen. This method includes the steps of disorder of the spleen. Preferably the GPCR polypeptide is (a) providing a transgenic non-human mammal (e.g., a in a cell or a cell free assay system. knock-out mouse) having a disruption in a nucleic acid 0249. In another aspect, the invention features a method molecule encoding a GPCR polypeptide substantially iden for determining whether a patient has an increased risk for tical to a polypeptide listed in Tables 27 and 33; (b) developing a disease or disorder of the spleen. The method contacting the transgenic non-human mammal with the includes the step of determining whether the patient has a candidate compound; and (c) measuring biological activity mutation in a gene encoding a polypeptide listed in Tables of the GPCR polypeptide in the transgenic non-human 27 and 33, wherein presence of the mutation indicates that mammal, wherein altered biological activity, relative to that the patient may have an increased risk for developing a of the transgenic non-human mammal not contacted with the disease or disorder of the spleen. compound, indicates that the candidate compound may be 0250). In a related aspect, the invention features another useful for the treatment of a disease or disorder of the spleen. method for determining whether a patient has an increased 0245. In yet another aspect, the invention features a risk for developing a disease or disorder of the spleen. This method for determining whether a candidate compound is a method includes the step of determining whether the patient compound that may be useful for the treatment of a disease has a polymorphism in a gene encoding a polypeptide listed US 2006/0134109 A1 Jun. 22, 2006 29 in Tables 27 and 33, wherein presence of the polymorphism disease, leukemia, lipogranulomas, lymphocytic leukemias, indicates that the patient may have an increased risk for lymphoma, malabsorption syndromes, malaria, malignant developing a disease or disorder of the spleen. lymphoma, megakaryoblastic leukemia, metastatic tumor, monocytic leukemias, mucopolysaccharidoses, multicentric 0251. In either of these two methods, the mutation or Castleman's disease, multiple myeloma, myelocytic leuke polymorphism is preferably associated with an alteration mias, myelofibrosis, myeloproliferative syndromes, neo (for example, a decrease) in the biological activity of the plasms, Niemann-Pick disease, non-Hodgkin’s lymphoma, polypeptide. parasitic disorders, parasitized red blood cells, peliosis, 0252) In another aspect, the invention features another polycythemia rubra Vera, portal vein congestion, portal vein method for determining whether a patient has an increased Stenosis, portal vein thrombosis, portal venous hypertension, risk for developing a disease or disorder of the spleen. The rheumatoid arthritis, right-sided cardiac failure, sarcoidosis, method includes measuring biological activity of a GPCR sarcoma, secondary amyloidosis, secondary myeloid meta polypeptide from the patient that is substantially identical to plasia, serum sickness, sickle-cell disease, splenic cysts, a polypeptide listed in Tables 27 and 33, wherein increased splenic infarction, splenic vein hypertension, splenic vein or decreased levels in the GPCR biological activity, relative Stenosis, splenic vein thrombosis, splenomegaly, storage to normal levels, indicate that the patient may have an diseases, systemic lupus erythematosus, systemic vasculiti increased risk for developing a disease or disorder of the des, T-cell chronic lymphocytic leukemia, thalasemia, spleen. thrombocytopenic purpura, thyrotoxicosis, trapping of immature hematologic cells, tuberculosis, tumorlike condi 0253) In still another aspect, the invention features yet tions, typhoid fever, vascular tumors, vasculitis, and viral another method for determining whether a patient has an infections. increased risk for developing a disease or disorder of the spleen. The method includes the step of measuring the 0255 In another aspect, the invention features a non patient’s expression levels of a polypeptide listed in Tables human mammal (e.g., a mouse), having a transgene that 27 and 33, wherein altered levels in the expression, relative includes a nucleic acid molecule encoding a GPCR polypep to normal, indicate that the patient has an increased risk for tide substantially identical to a polypeptide listed in Table developing a disease or disorder of the spleen. Preferably, 27. the expression levels are determined by measuring levels of 0256 In yet another aspect, the invention features a polypeptide or mRNA. non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a GPCR polypeptide sub 0254 Diseases of the spleen that can be treated or diag stantially identical to a polypeptide listed in Table 27. nosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 0257. In a related aspect, the invention features a cell abnormal immunoblastic proliferations of unknown origin, from a non-human mammal having a transgene that includes acute infections, acute parasitemias, agnogenic myeloid a nucleic acid molecule encoding a GPCR polypeptide metaplasia, amyloidosis, angioimmunoblastic lymphaden substantially identical to a polypeptide listed in Table 27. opathy, antibody-coated cells, asplenia, autoimmune dis 0258. In another aspect, the invention features a cell from eases, autoimmune hemolytic anemias, B-cell chronic lym a non-human mammal having a mutation in a nucleic acid phocytic leukemia and prolymphocytic leukemia, molecule encoding a GPCR polypeptide substantially iden babesiosis, bone marrow involvement by carcinoma, bru tical to a polypeptide listed in Table 27. cellosis, carcinoma, ceroid histiocytosis, chronic alcohol ism, chronic granulomatous disease, chronic hemolytic ane 0259. In another aspect, the invention features a method mias, chronic hemolytic disorders, chronic immunologic of preventing or treating a disease of the stomach including inflammatory disorders, chronic infections, chronic lympho introducing into a human an expression vector that includes cytic leukemia, chronic myelogenous leukemia, chronic a nucleic acid molecule encoding a GPCR polypeptide parasitemias, chronic uremia, cirrhosis, cold agglutinin dis substantially identical to a polypeptide listed in Tables 28 ease, congestive splenomegaly, cryoglobulinemia, dissemi and 33, operably linked to a promoter. nated tuberculosis, dysproteinemias, endocrine disorders, erythroblastic leukemia, erythropoiesis; essential thromb 0260. In still another aspect, the invention features a ocythemia, extramedullary hematopoiesis, Felty syndrome, method of treating or preventing a disease of the stomach fibrocongestive splenomegaly, fungal infections, gamm including administering to an animal (e.g., a human) a heavy-chain disease, Gaucher's disease, graft rejection, compound that modulates the biological activity of a GPCR granulomatous infiltration, hairy cell leukemia, hamartomas, polypeptide Substantially identical to a polypeptide listed in Hand-Schüller-Christian disease, hemangiomas, heman Tables 28 and 33. giosarcomas, hematologic disorders, hemoglobinopathies, 0261. In yet another aspect, the invention features a hemolytic anemias, hereditary elliptocytosis, hereditary method for determining whether a candidate compound is a spherocytosis, histiocytic medullary reticulosis, histiocyto compound that may be useful for the treatment of a disease sis X, Hodgkin’s disease, hyperSensitivity reactions, hyper or disorder of the stomach. This method includes the steps splenism, hyposplenism, idiopathic thrombocytopenic pur of (a) providing a GPCR polypeptide substantially identical pura, IgA deficiency, immune granulomas, immune to a polypeptide listed in Tables 28 and 33; (b) contacting the thrombocytopenia, immune thrombocytopenic purpura, GPCR polypeptide with the candidate compound; and (c) immunodeficiency disorders, infection associated hemoph measuring biological activity of the GPCR polypeptide, agocytic syndrome, infectious granulomas, infectious mono wherein altered biological activity, relative to that of the nucleosis, infective endocarditis, infiltrative splenomegaly, GPCR polypeptide not contacted with the compound, indi inflammatory pseudotumors, leishmaniasis, Leterer-Siwe cates that the candidate compound may be useful for the US 2006/0134109 A1 Jun. 22, 2006 30 treatment of a disease or disorder of the stomach. The GPCR listed in Tables 28 and 33; (b) contacting the polypeptide polypeptide can be in a cell or in a cell-free assay system. with the candidate compound; and (c) measuring the half 0262. In yet another aspect, the invention features a life of the polypeptide, wherein an alteration in the half-life method for determining whether a candidate compound is a of the polypeptide, relative to that of the polypeptide not compound that may be useful for the treatment of a disease contacted with the compound, indicates that the candidate or disorder of the stomach. This method includes the steps compound may be useful for the treatment of a disease or of (a) providing a transgenic non-human mammal (e.g., a disorder of the stomach. Preferably the GPCR polypeptide is knock-out mouse) having a disruption in a nucleic acid in a cell or a cell free assay system. molecule encoding a GPCR polypeptide substantially iden 0267 In another aspect, the invention features a method tical to a polypeptide listed in Tables 28 and 33; (b) for determining whether a patient has an increased risk for contacting the transgenic non-human mammal with the developing a disease or disorder of the stomach. The method candidate compound; and (c) measuring biological activity includes the step of determining whether the patient has a of the GPCR polypeptide in the transgenic non-human mutation in a gene encoding a polypeptide listed in Tables mammal, wherein altered biological activity, relative to that 28 and 33, wherein presence of the mutation indicates that of the transgenic non-human mammal not contacted with the the patient may have an increased risk for developing a compound, indicates that the candidate compound may be disease or disorder of the stomach. useful for the treatment of a disease or disorder of the stomach. 0268. In a related aspect, the invention features another method for determining whether a patient has an increased 0263. In yet another aspect, the invention features a risk for developing a disease or disorder of the stomach. This method for determining whether a candidate compound is a method includes the step of determining whether the patient compound that may be useful for the treatment of a disease has a polymorphism in a gene encoding a polypeptide listed or disorder of the stomach. This method includes the steps in Tables 28 and 33, wherein presence of the polymorphism of (a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the stomach. GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (b) contacting the transgenic 0269. In either of these two methods, the mutation or non-human mammal with the candidate compound; and (c) polymorphism is preferably associated with an alteration measuring biological activity of the GPCR polypeptide in (for example, a decrease) in the biological activity of the the transgenic non-human mammal, wherein altered biologi polypeptide. cal activity, relative to that of the transgenic non-human 0270. In another aspect, the invention features another mammal not contacted with the compound, indicates that the method for determining whether a patient has an increased candidate compound may be useful for the treatment of a risk for developing a disease or disorder of the stomach. The disease disease or disorder of the stomach. method includes measuring biological activity of a GPCR 0264. In still another aspect, the invention features polypeptide from the patient that is substantially identical to another method for determining whether a candidate com a polypeptide listed in Tables 28 and 33, wherein increased pound may be useful for the treatment of a disease or or decreased levels in the GPCR biological activity, relative disorder of the stomach. This method includes (a) providing to normal levels, indicate that the patient may have an a nucleic acid molecule comprising a promoter from a gene increased risk for developing a disease or disorder of the encoding a GPCR polypeptide listed in Tables 28 and 33, the stomach. promoter operably linked to a reporter system; (b) contact 0271 In still another aspect, the invention features yet ing the nucleic acid molecule with the candidate compound; another method for determining whether a patient has an and (c) measuring reporter activity, wherein altered reporter increased risk for developing a disease or disorder of the activity, relative to a nucleic acid molecule not contacted stomach. The method includes the step of measuring the with the compound, indicates that the candidate compound patient’s expression levels of a polypeptide listed in Tables may be useful for the treatment of a disease or disorder of 28 and 33, wherein altered levels in the expression, relative the stomach. to normal, indicate that the patient has an increased risk for 0265. In another aspect, the invention features yet developing a disease or disorder of the stomach. Preferably, another method for determining whether a candidate com the expression levels are determined by measuring levels of pound may be useful for the treatment of a disease or polypeptide or mRNA. disorder of the stomach. This method includes the steps of: 0272 Diseases of the stomach that can be treated or (a) providing a GPCR polypeptide substantially identical to diagnosed using the methods of the invention or for which a polypeptide listed in Tables 28 and 33; (b) contacting the candidate therapeutic compounds may be identified include polypeptide with the candidate compound; and (c) measur acute erosive gastropathy, acute gastric ulcers, adenocarci ing interaction of the candidate compound to the polypep nomas, adenomas, adenomatous polyps, advanced gastric tide. Interaction of the compound to the polypeptide indi cancer, ampullary carcinoma, atrophic gastritis, bacterial cates that the candidate compound may be useful for the gastritis, carcinoid turmors, carcinoma of the stomach, treatment of a disease or disorder of the stomach. chemical gastritis, chronic (nonerosive) gastritis, chronic 0266. In still another aspect, the invention features idiopathic gastritis, chronic nonatrophic gastritis, another method for determining whether a candidate com Chronkhite-Canada syndrome, congenital cysts, congenital pound may be useful for the treatment of a disease or diaphragmatic hernias, congenital diverticula, congenital disorder of the stomach. This method includes (a) providing duplications, congenital pyloric Stenosis, congestive gastr a GPCR polypeptide substantially identical to a polypeptide opathy, cyclic vomiting syndrome, decreased mucosal resis US 2006/0134109 A1 Jun. 22, 2006 tance to acid, diffuse or infiltrating adenocarcinoma, early 0279. In yet another aspect, the invention features a gastric cancer, emphysematous gastritis, endocrine cell method for determining whether a candidate compound is a hyperplasia, environmental gastritis, eosinophilic gastritis, compound that may be useful for the treatment of a disease eosinophilic gastroenteritis, epithelial polyps, erosive or disorder of the testes. This method includes the steps of (acute) gastritis, fundic gland polyps, fungal gastritis, gan (a) providing a GPCR polypeptide substantially identical to gliocytic paragangliomas, gastral antral vascular ectasia, a polypeptide listed in Tables 29 and 33; (b) contacting the gastric adenocarcinoma, gastric outlet obstruction (pyloric GPCR polypeptide with the candidate compound; and (c) Stenosis), gastric ulcers, gastritis, gastroesophageal reflux, measuring biological activity of the GPCR polypeptide, gastroparesis, granulomatous gastritis, H. Pylori infection, wherein altered biological activity, relative to that of the hamartomatous polyps, heterotopias, heterotopic pancreatic GPCR polypeptide not contacted with the compound, indi tissue, heterotopic polyps, hyperplastic gastropathy, hyper cates that the candidate compound may be useful for the plastic polyps, hypersecretion of acid, infectious gastritis, treatment of a disease or disorder of the testes. The GPCR inflammatory lesions of the stomach, inflammatory polyps, polypeptide can be in a cell or in a cell-free assay system. intestinal metaplasia, invasive carcinoma, ischemia, lei omyoma, linitis plastica, luminally acting toxic chemicals, 0280. In yet another aspect, the invention features a lymphocytic gastritis, lymphomas, malignant gastric stromal method for determining whether a candidate compound is a neoplasms, malignant lymphoma, malignant transformation compound that may be useful for the treatment of a disease of a benign gastric ulcer, Menentrier's disease (hypertrophic or disorder of the testes. This method includes the steps of gastritis, rugal hypertrophy), mesenchymal neoplasms, (a) providing a transgenic non-human mammal (e.g., a metastatic tumors, mucosal polyps, myoepithelial knock-out mouse) having a disruption in a nucleic acid adenomas, myoepithelial hamartomas, neoplasms, neuroen molecule encoding a GPCR polypeptide substantially iden docrine hyperplasias, neuroendocrine tumors, nonerosive tical to a polypeptide listed in Tables 29 and 33; (b) gastritis and stomach cancer, nonneoplastic polyps, parasitic contacting the transgenic non-human mammal with the gastritis, peptic ulcer disease, phlegmonous gastritis, plasma candidate compound; and (c) measuring biological activity cell gastritis, polypoid (fungating) adenocarcinoma, poorly of the GPCR polypeptide-in the transgenic non-human differentiated neuroendocrine carcinomas, precancerous mammal, wherein altered biological activity, relative to that lesions, Puetz-Jeghers syndrome, pyloric atresia, rapid gas of the transgenic non-human mammal not contacted with the tric emptying, reflux of bile, stress ulcers, stromal tumors, compound, indicates that the candidate compound may be Superficial gastritis, type A chronic gastritis (autoimmune useful for the treatment of a disease or disorder of the testes. gastritis and pernicious anemia), type B chronic gastritis 0281. In yet another aspect, the invention features a (chronic antral gastritis, H. Pylori gastritis), ulcerating method for determining whether a candidate compound is a adenocarcinoma, Vasculitis, viral gastritis, Xanthomatous compound that may be useful for the treatment of a disease gastritis, and Zollinger-Ellison syndrome. or disorder of the testes. This method includes the steps of 0273. In another aspect, the invention features a non (a) providing a transgenic non-human mammal (e.g., a human mammal (e.g., a mouse), having a transgene that mouse) overexpressing a nucleic acid molecule encoding a includes a nucleic acid molecule encoding a GPCR polypep GPCR polypeptide substantially identical to a polypeptide tide substantially identical to a polypeptide listed in Table listed in Tables 29 and 33; (b) contacting the transgenic 28. non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide in 0274. In yet another aspect, the invention features a the transgenic non-human mammal, wherein altered biologi non-human mammal (e.g., a mouse), having a mutation in a cal activity, relative to that of the transgenic non-human nucleic acid molecule encoding a GPCR polypeptide sub mammal not contacted with the compound, indicates that the stantially identical to a polypeptide listed in Table 28. candidate compound may be useful for the treatment of a 0275. In a related aspect, the invention features a cell disease disease or disorder of the testes. from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a GPCR polypeptide 0282. In still another aspect, the invention features substantially identical to a polypeptide listed in Table 28. another method for determining whether a candidate com pound may be useful for the treatment of a disease or 0276. In another aspect, the invention features a cell from disorder of the testes. This method includes (a) providing a a non-human mammal having a mutation in a nucleic acid nucleic acid molecule comprising a promoter from a gene molecule encoding a GPCR polypeptide substantially iden encoding a GPCR polypeptide listed in Tables 29 and 33, the tical to a polypeptide listed in Table 28. promoter operably linked to a reporter system; (b) contact 0277. In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the testes including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 29 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the testes. 0278 In still another aspect, the invention features a 0283. In another aspect, the invention features yet method of treating or preventing a disease of the testes another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the testes. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a Tables 29 and 33. polypeptide listed in Tables 29 and 33; (b) contacting the US 2006/0134109 A1 Jun. 22, 2006 32 polypeptide with the candidate compound; and (c) measur aberrant ducts of Haller, abnormal productions of hormones, ing interaction of the candidate compound to the polypep abnormalities of testicular descent, acute epididymoorhcitis, tide. Interaction of the compound to the polypeptide indi adenomatoid tumor, adenomatous hyperplasia of the rete cates that the candidate compound may be useful for the testis, adenovirus, administration of estrogens, adrenal rests, treatment of a disease or disorder of the testes. alcoholic cirrhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Brucella, cachexia, carcinoma in situ, 0284. In still another aspect, the invention features carcinoma of the rete testis, chlamydia, choriocarcinoma, another method for determining whether a candidate com choristomas, chronic fibrosing epididymoorchitis, coxsackie pound may be useful for the treatment of a disease or virus B, cryptorchidism, cystic dysplasia of the rete testis, disorder of the testes. This method includes (a) providing a cytomegalovirus, dystopia, E. coli, Echinococcus granulo GPCR polypeptide substantially identical to a polypeptide sus, ectopic testes, embryonal carcinoma, epididymoorchi listed in Tables 29 and 33; (b) contacting the polypeptide tis, Fournier's scrotal gangrene, fungal infection, germ cell with the candidate compound; and (c) measuring the half aplasia, germ cell neoplasms, gonadal dysgenesis, gonadal life of the polypeptide, wherein an alteration in the half-life stromal neoplasms, granulomatous orchitis, granulosa cell of the polypeptide, relative to that of the polypeptide not tumors, Haemophilus influenzae, HIV, hypergonadism, contacted with the compound, indicates that the candidate hypogonadotropic hypogonadism, hypopituitarism, compound may be useful for the treatment of a disease or hypospermatogenesis, hyrocele, idiopathic granulomatous disorder of the testes. Preferably the GPCR polypeptide is in orchitis, incomplete maturation arrest, infarction, infertility, a cell or a cell free assay system. inflammatory diseases, inflammatory lesions, interstitial 0285) In another aspect, the invention features a method (Leydig) cell tumors, Klinfelter's syndrome, latrogenic for determining whether a patient has an increased risk for lesions, Leydig cell tumors, malaknock outplakia, malignant developing a disease or disorder of the testes. The method lymphoma, malnutrition, maturation arrest of spermatogen includes the step of determining whether the patient has a esis, metastatic tumors, mixed germ cell tumors, mutation in a gene encoding a polypeptide listed in Tables monorchism, mumps orchitis, mycobacteria, Neisseria gon 29 and 33, wherein presence of the mutation indicates that orrhoeae, neoplasms, obstruction to outflow of semen, the patient may have an increased risk for developing a orchitis, parasitic infection, polyorchidism, radiation, Sal disease or disorder of the testes. monella, sarcoidosis, Schistosoma haematobium, semi 0286. In a related aspect, the invention features another noma, Sertoli cell tumors, sex cord stromal tumors, sperm method for determining whether a patient has an increased granuloma, Spermatocytic seminoma, syphilis, teratocarci risk for developing a disease or disorder of the testes. This noma, teratoma, testicular atrophy, testicular neoplasms, method includes the step of determining whether the patient testicular torsion, Treponema pallidum, tuberculous epididy has a polymorphism in a gene encoding a polypeptide listed moorchitis, tumors of nonspecific stroma, undescended tes in Tables 29 and 33, wherein presence of the polymorphism tes, uropathogens, varicocele, vascular disturbances, vascu indicates that the patient may have an increased risk for litis, viral infection, Wuchereria bancrofti, and yolk sac developing a disease or disorder of the testes. carcinoma. 0287. In either of these two methods, the mutation or 0291. In another aspect, the invention features a non polymorphism is preferably associated with an alteration human mammal (e.g., a mouse), having a transgene that (for example, a decrease) in the biological activity of the includes a nucleic acid molecule encoding a GPCR polypep polypeptide. tide substantially identical to a polypeptide listed in Table 29. 0288. In another aspect, the invention features another method for determining whether a patient has an increased 0292. In yet another aspect, the invention features a risk for developing a disease or disorder of the testes. The non-human mammal (e.g., a mouse), having a mutation in a method includes measuring biological activity of a GPCR nucleic acid molecule encoding a GPCR polypeptide sub polypeptide from the patient that is substantially identical to stantially identical to a polypeptide listed in Table 29. a polypeptide listed in Tables 29 and 33, wherein increased 0293. In a related aspect, the invention features a cell or decreased levels in the GPCR biological activity, relative from a non-human mammal having a transgene that includes to normal levels, indicate that the patient may have an a nucleic acid molecule encoding a GPCR polypeptide increased risk for developing a disease or disorder of the substantially identical to a polypeptide listed in Table 29. testes. 0294. In another aspect, the invention features a cell from 0289. In still another aspect, the invention features yet a non-human mammal having a mutation in a nucleic acid another method for determining whether a patient has an molecule encoding a GPCR polypeptide substantially iden increased risk for developing a disease or disorder of the tical to a polypeptide listed in Table 29. testes. The method includes the step of measuring the patient’s expression levels of a polypeptide listed in Tables 0295). In another aspect, the invention features a method 29 and 33, wherein altered levels in the expression, relative of preventing or treating a disease of the thymus including to normal, indicate that the patient has an increased risk for introducing into a human an expression vector that includes developing a disease or disorder of the testes. Preferably, the a nucleic acid molecule encoding a GPCR polypeptide expression levels are determined by measuring levels of substantially identical to a polypeptide listed in Tables 30 polypeptide or mRNA. and 33, operably linked to a promoter. 0290 Diseases of the testes that can be treated or diag 0296. In still another aspect, the invention features a nosed using the methods of the invention or for which method of treating or preventing a disease of the thymus candidate therapeutic compounds may be identified include including administering to an animal (e.g., a human) a US 2006/0134109 A1 Jun. 22, 2006

compound that modulates the biological activity of a GPCR pound may be useful for the treatment of a disease or polypeptide Substantially identical to a polypeptide listed in disorder of the thymus. This method includes the steps of: Tables 30 and 33. (a) providing a GPCR polypeptide substantially identical to 0297. In yet another aspect, the invention features a a polypeptide listed in Tables 30 and 33; (b) contacting the method for determining whether a candidate compound is a polypeptide with the candidate compound; and (c) measur compound that may be useful for the treatment of a disease ing interaction of the candidate compound to the polypep or disorder of the thymus. This method includes the steps of tide. Interaction of the compound to the polypeptide indi (a) providing a GPCR polypeptide substantially identical to cates that the candidate compound may be useful for the a polypeptide listed in Tables 30 and 33; (b) contacting the treatment of a disease or disorder of the thymus. GPCR polypeptide with the candidate compound; and (c) 0302) In still another aspect, the invention features measuring biological activity of the GPCR polypeptide, another method for determining whether a candidate com wherein altered biological activity, relative to that of the pound may be useful for the treatment of a disease or GPCR polypeptide not contacted with the compound, indi disorder of the thymus. This method includes (a) providing cates that the candidate compound may be useful for the a GPCR polypeptide substantially identical to a polypeptide treatment of a disease or disorder of the thymus. The GPCR listed in Tables 30 and 33; (b) contacting the polypeptide polypeptide can be in a cell or in a cell-free assay system. with the candidate compound; and (c) measuring the half 0298. In yet another aspect, the invention features a life of the polypeptide, wherein an alteration in the half-life method for determining whether a candidate compound is a of the polypeptide, relative to that of the polypeptide not compound that may be useful for the treatment of a disease contacted with the compound, indicates that the candidate or disorder of the thymus. This method includes the steps of compound may be useful for the treatment of a disease or (a) providing a transgenic non-human mammal (e.g., a disorder of the thymus. Preferably the GPCR polypeptide is knock-out mouse) having a disruption in a nucleic acid in a cell or a cell free assay system. molecule encoding a GPCR polypeptide substantially iden 0303. In another aspect, the invention features a method tical to a polypeptide listed in Tables 30 and 33; (b) for determining whether a patient has an increased risk for contacting the transgenic non-human mammal with the developing a disease or disorder of the thymus. The method candidate compound; and (c) measuring biological activity includes the step of determining whether the patient has a of the GPCR polypeptide in the transgenic non-human mutation in a gene encoding a polypeptide listed in Tables mammal, wherein altered biological activity, relative to that 30 and 33, wherein presence of the mutation indicates that of the transgenic non-human mammal not contacted with the the patient may have an increased risk for developing a compound, indicates that the candidate compound may be disease or disorder of the thymus. useful for the treatment of a disease or disorder of the 0304. In a related aspect, the invention features another thymus. method for determining whether a patient has an increased 0299. In yet another aspect, the invention features a risk for developing a disease or disorder of the thymus. This method for determining whether a candidate compound is a method includes the step of determining whether the patient compound that may be useful for the treatment of a disease has a polymorphism in a gene encoding a polypeptide listed or disorder of the thymus. This method includes the steps of in Tables 30 and 33, wherein presence of the polymorphism (a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the thymus. GPCR polypeptide substantially identical to a polypeptide 0305. In either of these two methods, the mutation or listed in Tables 30 and 33; (b) contacting the transgenic polymorphism is preferably associated with an alteration non-human mammal with the candidate compound; and (c) (for example, a decrease) in the biological activity of the measuring biological activity of the GPCR polypeptide in polypeptide. the transgenic non-human mammal, wherein altered biologi cal activity, relative to that of the transgenic non-human 0306 In another aspect, the invention features another mammal not contacted with the compound, indicates that the method for determining whether a patient has an increased candidate compound may be useful for the treatment of a risk for developing a disease or disorder of the thymus. The disease disease or disorder of the thymus. method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to 0300. In still another aspect, the invention features a polypeptide listed in Tables 30 and 33, wherein increased another method for determining whether a candidate com or decreased levels in the GPCR biological activity, relative pound may be useful for the treatment of a disease or to normal levels, indicate that the patient may have an disorder of the thymus. This method includes (a) providing increased risk for developing a disease or disorder of the a nucleic acid molecule comprising a promoter from a gene thymus. encoding a GPCR polypeptide listed in Tables 30 and 33, the 0307 In still another aspect, the invention features yet promoter operably linked to a reporter system; (b) contact another method for determining whether a patient has an ing the nucleic acid molecule with the candidate compound; increased risk for developing a disease or disorder of the and (c) measuring reporter activity, wherein altered reporter thymus. The method includes the step of measuring the activity, relative to a nucleic acid molecule not contacted patient’s expression levels of a polypeptide listed in Tables with the compound, indicates that the candidate compound 30 and 33, wherein altered levels in the expression, relative may be useful for the treatment of a disease or disorder of to normal, indicate that the patient has an increased risk for the thymus. developing a disease or disorder of the thymus. Preferably, 0301 In another aspect, the invention features yet the expression levels are determined by measuring levels of another method for determining whether a candidate com polypeptide or mRNA. US 2006/0134109 A1 Jun. 22, 2006 34

0308 Diseases of the thymus that can be treated or 0315. In yet another aspect, the invention features a diagnosed using the methods of the invention or for which method for determining whether a candidate compound is a candidate therapeutic compounds may be identified include compound that may be useful for the treatment of a disease accidental involution, acute accidental involution, acute or disorder of the thyroid. This method includes the steps of lymphoblastic leukemia of T cell type, agenesis, age-related (a) providing a GPCR polypeptide substantially identical to involution, anaplastic carcinoma, ataxia telangiectasia, atro a polypeptide listed in Tables 31 and 33; (b) contacting the phy, bacterial infections, bacterial mediastinitis, basaloid GPCR polypeptide with the candidate compound; and (c) carcinoma, bone marrow transplantation, Bruton’s agamma measuring biological activity of the GPCR polypeptide, globulinemia, carcinosarcoma, chronic accidental involu wherein altered biological activity, relative to that of the tion, clear cell carcinoma, cortical thymoma, cytomegalovi GPCR polypeptide not contacted with the compound, indi rus, DiGeorge syndrome, dysgenesis, dysplasia with pattern cates that the candidate compound may be useful for the similar to severe atrophy, dysplasia with pseudoglandular treatment of a disease or disorder of the thyroid. The GPCR appearance, dysplasia with Stromal conticomedullary differ polypeptide can be in a cell or in a cell-free assay system. entiation, ectopia, germ cell tumors, Grave's disease, his tiocytosis X, HIV, Hodgkin's disease, hyperplasia, infec 0316. In yet another aspect, the invention features a tious mononucleosis, involution, lymphoblastic lymphoma method for determining whether a candidate compound is a of T-cell type, lymphoepithelioma-like carcinoma, lympho compound that may be useful for the treatment of a disease follicular thymitis, maldescent, malignant lymphomas, or disorder of the thyroid. This method includes the steps of malignant thymoma, measles giant cell pneumonia, medul (a) providing a transgenic non-human mammal (e.g., a lary thymoma, mixed (composite) thymoma, mucoepider knock-out mouse) having a disruption in a nucleic acid moid carcinoma, myasthenia gravis, neonatal syphilis, neo molecule encoding a GPCR polypeptide substantially iden plasms, Omenn's syndrome, predominantly cortical tical to a polypeptide listed in Tables 31 and 33; (b) (organoid) thymoma, primary mediastinal B-cell lymphoma contacting the transgenic non-human mammal with the of high-grade malignancy, sarcomatoid carcinoma, semi candidate compound; and (c) measuring biological activity noma, severe combined immunodeficiency, short limb of transgenic non-human mammal, wherein altered biologi dwarfism, simple dysplasia, Small cell carcinoma, Small-cell cal activity, relative to that of the GPCR transgenic non B-cell lymphoma of MALT type, squamous cell carcinoma, human mammal not contacted with the compound, indicates systemic lupus erythematosus, teratoma, thymic carcinoid, that the candidate compound may be useful for the treatment thymic carcinoma, thymic cysts, thymic epithelial cysts, of a disease or disorder of the thyroid. thymic epithelial tumorw, thymic neoplasms, thymitis with 0317. In yet another aspect, the invention features a diffuse B-cell infiltrations, thymolipoma, thymoma, true method for determining whether a candidate compound is a thymic hyperplasia, Varicella-Zoster, viral infections, well compound that may be useful for the treatment of a disease differentiated thymic carcinoma, and Wiscott-Aldrich syn or disorder of the thyroid. This method includes the steps of drome. (a) providing a transgenic non-human mammal (e.g., a 0309. In another aspect, the invention features a non mouse) overexpressing a nucleic acid molecule encoding a human mammal (e.g., a mouse), having a transgene that GPCR polypeptide substantially identical to a polypeptide includes a nucleic acid molecule encoding a GPCR polypep listed in Tables 31 and 33; (b) contacting the transgenic tide substantially identical to a polypeptide listed in Table non-human mammal with the candidate compound; and (c) 3O. measuring biological activity of the GPCR polypeptide in 0310. In yet another aspect, the invention features a the transgenic non-human mammal, wherein altered biologi non-human mammal (e.g., a mouse), having a mutation in a cal activity, relative to that of the transgenic non-human nucleic acid molecule encoding a GPCR polypeptide sub mammal not contacted with the compound, indicates that the stantially identical to a polypeptide listed in Table 30. candidate compound may be useful for the treatment of a 0311. In a related aspect, the invention features a cell disease disease or disorder of the thyroid. from a non-human mammal having a transgene that includes 0318. In still another aspect, the invention features a nucleic acid molecule encoding a GPCR polypeptide another method for determining whether a candidate com substantially identical to a polypeptide listed in Table 30. pound may be useful for the treatment of a disease or 0312. In another aspect, the invention features a cell from disorder of the thyroid. This method includes (a) providing a non-human mammal having a mutation in a nucleic acid a nucleic acid molecule comprising a promoter from a gene molecule encoding a GPCR polypeptide substantially iden encoding a GPCR polypeptide listed in Tables 31 and 33, the tical to a polypeptide listed in Table 30. promoter operably linked to a reporter system; (b) contact 0313. In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the thyroid including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 31 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the thyroid. 0314. In still another aspect, the invention features a 0319. In another aspect, the invention features yet method of treating or preventing a disease of the thyroid another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the thyroid. This method includes the steps of: (a) polypeptide Substantially identical to a polypeptide listed in providing a GPCR polypeptide substantially identical to a Tables 31 and 33. polypeptide listed in Tables 31 and 33; (b) contacting the US 2006/0134109 A1 Jun. 22, 2006 polypeptide with the candidate compound; and (c) measur aberrant thyroid glands, accessory thyroid glands, adenoma ing interaction of the candidate compound to the polypep with bizarre nuclei, agenesis, amphicrine variant of medul tide. Interaction of the compound to the polypeptide indi lary carcinoma, anaplastic (undifferentiated) carcinoma, cates that the candidate compound may be useful for the aplasia, atrophic thyroiditis, atypical adenoma, autoimmune treatment of a disease or disorder of the thyroid. thyroiditis, carcinoma, C-cell hyperplasia, clear cell tumors, clear cell variant of medullary carcinoma, colloid adenoma, 0320 In still another aspect, the invention features columnar variant of papillary carcinoma, congentital another method for determining whether a candidate com hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse pound may be useful for the treatment of a disease or Sclerosing variant of papillary carcinoma, dyshormonogenic disorder of the thyroid. This method includes (a) providing goiter, embryonal adenoma, encapsulated variant of papil a GPCR polypeptide substantially identical to a polypeptide lary carcinome, endemic cretinism, endemic goiter, enzyme listed in Tables 31 and 33; (b) contacting the polypeptide deficiency, fetal adenoma, follicular adenoma, follicular with the candidate compound; and (c) measuring the half carcinoma, follicular variant of medullary carcinoma, folli life of the polypeptide, wherein an alteration in the half-life cular variant of papillary carcinoma, fungal infection, giant of the polypeptide, relative to that of the polypeptide not cell variant of medullary carcinoma, goiter induced by contacted with the compound, indicates that the candidate antithyroid agents, goitrous hypothyroidism, Graves' dis compound may be useful for the treatment of a disease or ease, Hashimoto's autoimmune thyroiditis, Hirthle cell disorder of the thyroid. Preferably the GPCR polypeptide is (oncocytic) adenoma, hyalinized trabecular adenoma, in a cell or a cell free assay system. hyperthyroidism, hypothyroid cretinism, hypothyroidism, 0321) In another aspect, the invention features a method iodine deficiency, juvenile thyroiditis, latrogenic hypothy for determining whether a patient has an increased risk for roidism, lingual thyroid glands, malignant lymphoma, med developing a disease or disorder of the thyroid. The method ullary carcinoma, melanocytic variant of medullary carci includes the step of determining whether the patient has a noma, mesenchymal tumors, metastatic tumors, minimally mutation in a gene encoding a polypeptide listed in Tables invasive follicular carcinoma, mixed medullary and follicu 31 and 33, wherein presence of the mutation indicates that lar carcinoma, mixed medullary and papillary carcinoma, the patient may have an increased risk for developing a mucinous carcinoma, mucoepidermoid carcinoma, multin disease or disorder of the thyroid. odular goiter, myxedema, neoplasms, neurologic cretinism, nonspecific lymphocytic (simple chronic) thyroiditis, onco 0322. In a related aspect, the invention features another cytic variant of medullary carcinoma, palpation thyroiditis, method for determining whether a patient has an increased papillary carcinoma, papillary microcarcinoma, papillary risk for developing a disease or disorder of the thyroid. This variant of medullary carcinoma, partial agenesis, pituitary method includes the step of determining whether the patient thyrotropic adenoma, poorly differentiated carcinoma, pri has a polymorphism in a gene encoding a polypeptide listed mary hypothyroidism, pseudopapillary variant of medullary in Tables 31 and 33, wherein presence of the polymorphism carcinoma, Riedel's thyroiditis, Sclerosing mucoepidermoid indicates that the patient may have an increased risk for carcinoma with eosinophilia, silent thyroiditis, simple developing a disease or disorder of the thyroid. adenoma, Small cell variant of medullary carcinoma, Solitary 0323 In either of these two methods, the mutation or thyroid nodule, sporadic goiter, squamous cell carcinoma, polymorphism is preferably associated with an alteration squamous variant of medullary carcinoma, Subacute throidi (for example, a decrease) in the biological activity of the tis (DeCuervain, granulomatous, giant cell thyroiditis), tall polypeptide. cell variant of papillary carcinoma, tertiary syphilis, thyro 0324. In another aspect, the invention features another glossal duct cyst, thyroid agenesis, thyroid nodules, thy method for determining whether a patient has an increased roiditis, thyrotoxicosis, toxic adenoma, toxic multinodular risk for developing a disease or disorder of the thyroid. The goiter, toxic nodular goiter (Plummer's disease), tuberculo method includes measuring biological activity of a GPCR sis, tubular variant of medullary carcinoma, and widely polypeptide from the patient that is substantially identical to invasive follicular carcinoma. a polypeptide listed in Tables 31 and 33, wherein increased 0327 In another aspect, the invention features a non or decreased levels in the GPCR biological activity, relative human mammal (e.g., a mouse), having a transgene that to normal levels, indicate that the patient may have an includes a nucleic acid molecule encoding a GPCR polypep increased risk for developing a disease or disorder of the tide substantially identical to a polypeptide listed in Table thyroid. 31. 0325 In still another aspect, the invention features yet 0328. In yet another aspect, the invention features a another method for determining whether a patient has an non-human mammal (e.g., a mouse), having a mutation in a increased risk for developing a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub thyroid. The method includes the step of measuring the stantially identical to a polypeptide listed in Table 31. patient’s expression levels of a polypeptide listed in Tables 31 and 33, wherein altered levels in the expression, relative 0329. In a related aspect, the invention features a cell to normal, indicate that the patient has an increased risk for from a non-human mammal having a transgene that includes developing a disease or disorder of the thyroid. Preferably, a nucleic acid molecule encoding a GPCR polypeptide the expression levels are determined by measuring levels of substantially identical to a polypeptide listed in Table 31. polypeptide or mRNA. 0330. In another aspect, the invention features a cell from 0326 Diseases of the thyroid that can be treated or a non-human mammal having a mutation in a nucleic acid diagnosed using the methods of the invention or for which molecule encoding a GPCR polypeptide substantially iden candidate therapeutic compounds may be identified include tical to a polypeptide listed in Table 31. US 2006/0134109 A1 Jun. 22, 2006 36

0331 In another aspect, the invention features a method ing the nucleic acid molecule with the candidate compound; of preventing or treating a disease of the uterus including and (c) measuring reporter activity, wherein altered reporter introducing into a human an expression vector that includes activity, relative to a nucleic acid molecule not contacted a nucleic acid molecule encoding a GPCR polypeptide with the compound, indicates that the candidate compound substantially identical to a polypeptide listed in Tables 32 may be useful for the treatment of a disease or disorder of and 33, operably linked to a promoter. the uterus. 0332. In still another aspect, the invention features a 0337. In another aspect, the invention features yet method of treating or preventing a disease of the uterus another method for determining whether a candidate com including administering to an animal (e.g., a human) a pound may be useful for the treatment of a disease or compound that modulates the biological activity of a GPCR disorder of the uterus. polypeptide Substantially identical to a polypeptide listed in 0338. This method includes the steps of: (a) providing a Tables 32 and 33. GPCR polypeptide substantially identical to a polypeptide 0333. In yet another aspect, the invention features a listed in Tables 32 and 33; (b) contacting the polypeptide method for determining whether a candidate compound is a with the candidate compound; and (c) measuring interaction compound that may be useful for the treatment of a disease of the candidate compound to the polypeptide. Interaction of or disorder of the uterus. This method includes the steps of the compound to the polypeptide indicates that the candidate (a) providing a GPCR polypeptide substantially identical to compound may be useful for the treatment of a disease or a polypeptide listed in Tables 32 and 33; (b) contacting the disorder of the uterus. GPCR polypeptide with the candidate compound; and (c) 0339. In still another aspect, the invention features measuring biological activity of the GPCR polypeptide, another method for determining whether a candidate com wherein altered biological activity, relative to that of the pound may be useful for the treatment of a disease or GPCR polypeptide not contacted with the compound, indi disorder of the uterus. This method includes (a) providing a cates that the candidate compound may be useful for the GPCR polypeptide substantially identical to a polypeptide treatment of a disease or disorder of the uterus. The GPCR listed in Tables 32 and 33; (b) contacting the polypeptide polypeptide can be in a cell or in a cell-free assay system. with the candidate compound; and (c) measuring the half 0334. In yet another aspect, the invention features a life of the polypeptide, wherein an alteration in the half-life method for determining whether a candidate compound is a of the polypeptide, relative to that of the polypeptide not compound that may be useful for the treatment of a disease contacted with the compound, indicates that the candidate or disorder of the uterus. This method includes the steps of compound may be useful for the treatment of a disease or (a) providing a transgenic non-human mammal (e.g., a disorder of the uterus. Preferably the GPCR polypeptide is knock-out mouse) having a disruption in a nucleic acid in a cell or a cell free assay system. molecule encoding a GPCR polypeptide substantially iden tical to a polypeptide listed in Tables 32 and 33; (b) 0340. In another aspect, the invention features a method contacting transgenic non-human mammal with the candi for determining whether a patient has an increased risk for date compound; and (c) measuring biological activity of the developing a disease or disorder of the uterus. The method GPCR transgenic non-human mammal, wherein altered bio includes the step of determining whether the patient has a logical activity, relative to that of the transgenic non-human mutation in a gene encoding a polypeptide listed in Tables mammal not contacted with the compound, indicates that the 32 and 33, wherein presence of the mutation indicates that candidate compound may be useful for the treatment of a the patient may have an increased risk for developing a disease or disorder of the uterus. disease or disorder of the uterus. 0335) In yet another aspect, the invention features a 0341 In a related aspect, the invention features another method for determining whether a candidate compound is a method for determining whether a patient has an increased compound that may be useful for the treatment of a disease risk for developing a disease or disorder of the uterus. This or disorder of the uterus. This method includes the steps of method includes the step of determining whether the patient (a) providing a transgenic non-human mammal (e.g., a has a polymorphism in a gene encoding a polypeptide listed mouse) overexpressing a nucleic acid molecule encoding a in Tables 32 and 33, wherein presence of the polymorphism GPCR polypeptide substantially identical to a polypeptide indicates that the patient may have an increased risk for listed in Tables 32 and 33; (b) contacting the transgenic developing a disease or disorder of the uterus. non-human mammal with the candidate compound; and (c) 0342. In either of these two methods, the mutation or measuring biological activity of the GPCR polypeptide in polymorphism is preferably associated with an alteration the transgenic non-human mammal, wherein altered biologi (for example, a decrease) in the biological activity of the cal activity, relative to that of the transgenic non-human polypeptide. mammal not contacted with the compound, indicates that the 0343. In another aspect, the invention features another candidate compound may be useful for the treatment of a method for determining whether a patient has an increased disease disease or disorder of the uterus. risk for developing a disease or disorder of the uterus. The 0336. In still another aspect, the invention features method includes measuring biological activity of a GPCR another method for determining whether a candidate com polypeptide from the patient that is substantially identical to pound may be useful for the treatment of a disease or a polypeptide listed in Tables 32 and 33, wherein increased disorder of the uterus. This method includes (a) providing a or decreased levels in the GPCR biological activity, relative nucleic acid molecule comprising a promoter from a gene to normal levels, indicate that the patient may have an encoding a GPCR polypeptide listed in Tables 32 and 33, the increased risk for developing a disease or disorder of the promoter operably linked to a reporter system; (b) contact uterus. US 2006/0134109 A1 Jun. 22, 2006 37

0344) In still another aspect, the invention features yet 0346. In another aspect, the invention features a non another method for determining whether a patient has an human mammal (e.g., a mouse), having a transgene that increased risk for developing a disease or disorder of the includes a nucleic acid molecule encoding a GPCR polypep uterus. The method includes the step of measuring the tide substantially identical to a polypeptide listed in Table patient’s expression levels of a polypeptide listed in Tables 32. 32 and 33, wherein altered levels in the expression, relative 0347 In yet another aspect, the invention features a to normal, indicate that the patient has an increased risk for non-human mammal (e.g., a mouse), having a mutation in a developing a disease or disorder of the uterus. Preferably, the nucleic acid molecule encoding a GPCR polypeptide sub expression levels are determined by measuring levels of stantially identical to a polypeptide listed in Table 32. polypeptide or mRNA. 0348. In a related aspect, the invention features a cell 0345 Diseases of the uterus that can be treated or diag from a non-human mammal having a transgene that includes nosed using the methods of the invention or for which a nucleic acid molecule encoding a GPCR polypeptide candidate therapeutic compounds may be identified include substantially identical to a polypeptide listed in Table 32. acute cerviciitis, acute endometritis, adenocanthoma, adeno 0349. In another aspect, the invention features a cell from carcinoma, adenocarcinoma in situ, adenoid cystic carci a non-human mammal having a mutation in a nucleic acid noma, adenomatoid tumor, adenomyoma, adenomyosis molecule encoding a GPCR polypeptide substantially iden (endometriosis interna), adenosquamous carcinoma, ame tical to a polypeptide listed in Table 32. biasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hyperplasia, benign polypoid lesions, 0350. In another aspect, the invention features a method benign stromal nodule, carcinoid tumors, carcinoma in situ, of preventing or treating a disease of the pancreas including cervical intraepithelial neoplasia, chiamydia, chronic cervi introducing into a human an expression vector that includes citis, chronic nonspecific endometritis, ciliated (tubal) meta a nucleic acid molecule encoding a GPCR polypeptide plasia, clear cell adenocarcinoma, clear cell carcinoma, clear substantially identical to a polypeptide listed in Table 1 cell metaplasia, complex hyperplasia with atypia, complex operably linked to a promoter. hyperplasia without atypia, condyloma aduminatum, con 0351. In still another aspect, the invention features a genital abnormalities, corpus cancer syndrome, cystic hyper method of treating or preventing a disease of the pancreas plasia, dysfunctional uterine bleeding, dysmenorrhea, dys including administering to an animal (e.g., a human) a plasia of the cervix (cervical intraepithelial neoplasia, compound that modulates the biological activity of a GPCR squamous intraepithelial lesion), endocervical adenocarci polypeptide Substantially identical to a polypeptide listed in noma, endocervical polyp, endolymphatic stromal myosis, Table 1. endometrial adenocarcinoma, endometrial carcinoma, endometrial hyperplasia, endometrial polyps, endometrial 0352. In yet another aspect, the invention features a stromal neoplasms, endometriosis, endometritis, method for determining whether a candidate compound is a endometroid (pure) adenocarcinoma of the endometrium, compound that may be useful for the treatment of a disease endometroid adenocarcinoma with squamous differentia or disorder of the pancreas. This method includes the steps tion, eosinophilic metaplasia, epimenorrhea, exogenous of (a) providing a GPCR polypeptide substantially identical progestational hormone effect, extrauterine endometriosis to a polypeptide listed in Table 1; (b) contacting the GPCR (endometriosis externia), gestational trophoplastic disease, polypeptide with the candidate compound; and (c) measur gonorrhea, hemangioma, herpes simplex virus type 2, high ing biological activity of the GPCR polypeptide, wherein grade squamous intraepithelial lesion, human papillomavi altered biological activity, relative to that of the GPCR rus, hyperplasia, inadequate luteal phase, infertility, inflam polypeptide not contacted with the compound, indicates that matory cervical lesions, inflammatory lesions of the the candidate compound may be useful for the treatment of endometrium, intravenous leiomyomatosis, invasive carci a disease or disorder of the pancreas. The GPCR polypeptide noma of cervix, invasive squamous cell carcinoma, lei can be in a cell or in a cell-free assay system. omyoma, leiomyosarcoma, lipoma, low-grade squamous 0353. In yet another aspect, the invention features a intraepithelial lesion, malignant mixed mesodermal (Mulle method for determining whether a candidate compound is a rian) tumor, menorrhagia, metaplasia, metastasizing lei compound that may be useful for the treatment of a disease omyoma, metastatic carcinoma, microglandular hyperplasia, or disorder of the pancreas. This method includes the steps microinvasive carcinoma, microinvasive squamous cell car of (a) providing a transgenic non-human mammal (e.g., a cinoma, mucinous adenocarcinoma, mucinous metaplasia, knock-out mouse) having a disruption in a nucleic acid neoplasms of the cervix, neoplasms of the endometrium, molecule encoding a GPCR polypeptide substantially iden neoplasms of the myometrium, nonneoplastic cervical pro tical to a polypeptide listed in Table 1; (b) contacting the liferations, papillary synctial metaplasia, papillomna pelvic transgenic non-human mammal with the candidate com inflammatory disease, peritoneal leiomyomatosis, persistent pound; and (c) measuring biological activity of the GPCR luteal phase, postmenopausal bleeding, serous papillary polypeptide in the transgenic non-human mammal, wherein adenocarcinoma, simple hyperplasia with atypia, simple altered biological activity, relative to that of the transgenic hyperplasia without atypia, spontaneous abortion, Squamous non-human mammal not contacted with the compound, carcinoma, squamous cell neoplasia, squamous intraepithe indicates that the candidate compound may be useful for the lial lesions, squamous metaplasia, squamous metaplasia treatment of a disease or disorder of the pancreas. (acanthosis), Stromal sarcoma, tuberculous endometritis, unopposed estrogen effect, uterine leiomyomata, Verrucou 0354) In yet another aspect, the invention features a carcinoma, Vestigial and heterotopic structures, villoglandu method for determining whether a candidate compound is a lar papillary adenocarcinoma, and viral endometritis. compound that may be useful for the treatment of a disease US 2006/0134109 A1 Jun. 22, 2006

or disorder of the pancreas. This method includes the steps tide listed in Table 1, wherein presence of the polymorphism of (a) providing a transgenic non-human mammal (e.g., a indicates that the patient may have an increased risk for mouse) overexpressing a nucleic acid molecule encoding a developing a disease or disorder of the pancreas. GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic 0360. In either of these two methods, the mutation or non-human mammal with the candidate compound; and (c) polymorphism is preferably associated with an alteration measuring biological activity of the GPCR polypeptide in (for example, a decrease) in the biological activity of the the transgenic non-human mammal, wherein altered biologi polypeptide. cal activity, relative to that of the transgenic non-human 0361. In another aspect, the invention features another mammal not contacted with the compound, indicates that the method for determining whether a patient has an increased candidate compound may be useful for the treatment of a risk for developing a disease or disorder of the pancreas. The disease or disorder of the pancreas. method includes measuring biological activity of a GPCR 0355. In still another aspect, the invention features polypeptide from the patient that is substantially identical to another method for determining whether a candidate com a polypeptide listed in Table 1, wherein increased or pound may be useful for the treatment of a disease or decreased levels in the GPCR biological activity, relative to disorder of the pancreas. This method includes (a) providing normal levels, indicates that the patient has an increased risk a nucleic acid molecule comprising a promoter from a gene for developing a disease or disorder of the pancreas. encoding a GPCR polypeptide listed in Table 1, the pro 0362. In still another aspect, the invention features yet moter operably linked to a reporter system; (b) contacting another method for determining whether a patient has an the nucleic acid molecule with the candidate compound; and increased risk for developing a disease or disorder of the (c) measuring reporter activity, wherein altered reporter pancreas. The method includes the step of measuring the activity, relative to a nucleic acid molecule not contacted patient’s expression levels of a polypeptide listed in Table 1, with the compound, indicates that the candidate compound wherein altered levels in the expression, relative to normal, may be useful for the treatment of a disease or disorder of indicate that the patient has an increased risk for developing the pancreas. a disease or disorder of the pancreas. Preferably, the expres 0356. In another aspect, the invention features yet sion levels are determined by measuring levels of polypep another method for determining whether a candidate com tide or mRNA. pound may be useful for the treatment of a disease or 0363 Diseases of the pancreas that can be treated or disorder of the pancreas. This method includes the steps of: diagnosed using the methods of the invention or for which (a) providing a GPCR polypeptide substantially identical to candidate therapeutic compounds may be identified include a polypeptide listed in Table 1; (b) contacting the polypep ACTHoma, acute pancreatitis, adult onset diabetes, annulare tide with the candidate compound; and (c) measuring inter pancreas, carcinoid syndrome, carcinoid tumors, carcinoma action of the candidate compound to the polypeptide. Inter of the pancreas, chronic pancreatitis, congenital cysts, Cush action of the compound to the polypeptide indicates that the ing's syndrome, cystadenocarcinoma, cystic fibrosis (muco candidate compound may be useful for the treatment of a viscidosis, fibrocystic disease), diabetes mellitus, ectopic disease or disorder of the pancreas. pancreatic tissue, gastinoma, gastrin excess, glucagon 0357. In still another aspect, the invention features excess, glucagonomas, GRFomas, hereditary pancreatitis, another method for determining whether a candidate com hyperinsulinism, impaired insulin release, infected pancre pound may be useful for the treatment of a disease or atic necrosis, insulin resistance, insulinomas, islet cell disorder of the pancreas. This method includes (a) providing hyperplasia, islet cell neoplasms, juvenile onset diabetes, a GPCR polypeptide substantially identical to a polypeptide macroamylasernia, maldevelopment of the pancreas, matu listed in Table 1; (b) contacting the polypeptide with the rity-onset diabetes of the young, metastatic neoplasms, candidate compound; and (c) measuring the half-life of the mucinous cystadenoma, neoplastic cysts, nonfunctional pan polypeptide, wherein an alteration in the half-life of the creatic endocrine tumors, pancreas divisum, pancreatic polypeptide, relative to that of the polypeptide not contacted abcess, pancreatic cancer, pancreatic cholera, pancreatic with the compound, indicates that the candidate compound cysts, pancreatic endocrine tumor causing carcinoid syn may be usefull for the treatment of a disease or disorder of drome, pancreatic endocrine tumor causing hypercalcemia, the pancreas. Preferably the GPCR polypeptide is in a cell pancreatic endocrine tumors, pancreatic exocrine insuffi or a cell free assay system. ciency, pancreatic pleural effusion, pancreatic polypeptide excess, pancreatic pseudocyst, pancreatic trauma, pancre 0358 In another aspect, the invention features a method atogenous ascites, serous cystadenoma, Shwachman’s Syn for determining whether a patient has an increased risk for drome. Somatostatin excess. Somatostatinoma syndrome, developing a disease or disorder of the pancreas. The traumatic pancreatitis, type 1 (insulin-dependent) diabetes, method includes the step of determining whether the patient type 2 (non-insulin-dependent) diabetes, vasoactive intesti has a mutation in a gene encoding a polypeptide listed in nal polypeptide excess, VIPomas, Zollinger-Ellison syn Table 1, wherein presence of the mutation indicates that the drome. patient has an increased risk for developing a disease or disorder of the pancreas. 0364. In another aspect, the invention features a non 0359. In a related aspect, the invention features another human mammal (e.g., a mouse), having a transgene that method for determining whether a patient has an increased includes a nucleic acid molecule encoding a GPCR polypep risk for developing a disease or disorder of the pancreas. tide substantially identical to a polypeptide listed in Table 1. This method includes the step of determining whether the 0365. In yet another aspect, the invention features a patient has a polymorphism in a gene encoding a polypep non-human mammal (e.g., a mouse), having a mutation in a US 2006/0134109 A1 Jun. 22, 2006 39 nucleic acid molecule encoding a GPCR polypeptide sub polypeptide in the transgenic non-human mammal, wherein stantially identical to a polypeptide listed in Table 1. altered biological activity, relative to that of the transgenic 0366. In a related aspect, the invention features a cell non-human mammal not contacted with the compound, from a non-human mammal having a transgene that includes indicates that the candidate compound may be useful for the a nucleic acid molecule encoding a GPCR polypeptide treatment of a disease or disorder of the bone and joints. substantially identical to a polypeptide listed in Table 1. 0373) In still another aspect, the invention features another method for determining whether a candidate com 0367. In another aspect, the invention features a cell from pound may be useful for the treatment of a disease or a non-human mammal having a mutation in a nucleic acid disorder of the bone and joints. This method includes (a) molecule encoding a GPCR polypeptide substantially iden providing a nucleic acid molecule comprising a promoter tical to a polypeptide listed in Table 1. from a gene encoding a GPCR polypeptide listed in Table 1, 0368. In another aspect, the invention features a method the promoter operably linked to a reporter system; (b) of preventing or treating a disease of the bone and joints contacting the nucleic acid molecule with the candidate including introducing into a human an expression vector that compound; and (c) measuring reporter activity, wherein includes a nucleic acid molecule encoding a GPCR polypep altered reporter activity, relative to a nucleic acid molecule tide substantially identical to a polypeptide listed in Table I not contacted with the compound, indicates that the candi operably linked to a promoter. date compound may be useful for the treatment of a disease or disorder of the bone and joints. 0369. In still another aspect, the invention features a method of treating or preventing a disease of the bone and 0374. In another aspect, the invention features yet joints including administering to an animal (e.g., a human) another method for determining whether a candidate com a compound that modulates the biological activity of a pound may be useful for the treatment of a disease or GPCR polypeptide substantially identical to a polypeptide disorder of the bone and joints. This method includes the listed in Table 1. steps of: (a) providing a GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the 0370. In yet another aspect, the invention features a polypeptide with the candidate compound; and (c) measur method for determining whether a candidate compound is a ing interaction of the candidate compound to the polypep compound that may be useful for the treatment of a disease tide. Interaction of the compound to the polypeptide indi or disorder of the bone and joints. This method includes the cates that the candidate compound may be useful for the steps of (a) providing a GPCR polypeptide substantially treatment of a disease or disorder of the bone and joints. identical to a polypeptide listed in Table 1; (b) contacting the 0375. In still another aspect, the invention features GPCR polypeptide with the candidate compound; and (c) another method for determining whether a candidate com measuring biological activity of the GPCR polypeptide, pound may be useful for the treatment of a disease or wherein altered biological activity, relative to that of the disorder of the bone and joints. This method includes (a) GPCR polypeptide not contacted with the compound, indi providing a GPCR polypeptide substantially identical to a cates that the candidate compound may be useful for the polypeptide listed in Table 1; (b) contacting the polypeptide treatment of a disease or disorder of the bone and joints. The with the candidate compound; and (c) measuring the half GPCR polypeptide can be in a cell or in a cell-free assay life of the polypeptide, wherein an alteration in the half-life system. of the polypeptide, relative to that of the polypeptide not 0371. In yet another aspect, the invention features a contacted with the compound, indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of a disease disorder of the bone and joints. Preferably the GPCR or disorder of the bone and joints. This method includes the polypeptide is in a cell or a cell free assay system. steps of (a) providing a transgenic non-human mammal 0376. In another aspect, the invention features a method (e.g., a knock-out mouse) having a disruption in a nucleic for determining whether a patient has an increased risk for acid molecule encoding a GPCR polypeptide substantially developing a disease or disorder of the bone and joints. The identical to a polypeptide listed in Table 1; (b) contacting the method includes the step of determining whether the patient transgenic non-human mammal with the candidate com has a mutation in a gene encoding a polypeptide listed in pound; and (c) measuring biological activity of the GPCR Table 1, wherein presence of the mutation indicates that the polypeptide in the transgenic non-human mammal, wherein patient has an increased risk for developing a disease or altered biological activity, relative to that of the transgenic disorder of the bone and joints. non-human mammal not contacted with the compound, 0377. In a related aspect, the invention features another indicates that the candidate compound may be useful for the method for determining whether a patient has an increased treatment of a disease or disorder of the bone and joints. risk for developing a disease or disorder of the bone and 0372. In yet another aspect, the invention features a joints. This method includes the step of determining whether method for determining whether a candidate compound is a the patient has a polymorphism in a gene encoding a compound that may be useful for the treatment of a disease polypeptide listed in Table 1, wherein presence of the or disorder of the bone and joints. This method includes the polymorphism indicates that the patient may have an steps of (a) providing a transgenic non-human mammal increased risk for developing a disease or disorder of the (e.g., a mouse) overexpressing a nucleic acid molecule bone and joints. encoding a GPCR polypeptide substantially identical to a 0378. In either of these two methods, the mutation or polypeptide listed in any one of Table 1; (b) contacting the polymorphism is preferably associated with an alteration transgenic non-human mammal with the candidate com (for example, a decrease) in the biological activity of the pound; and (c) measuring biological activity of the GPCR polypeptide. US 2006/0134109 A1 Jun. 22, 2006 40

0379. In another aspect, the invention features another thalassemia, Tietze's syndrome, tuberculosis of bone, tuber method for determining whether a patient has an increased culous arthritis, unicameral bone cyst (Solitary bone cyst), risk for developing a disease or disorder of the bone and viral arthritis. joints. The method includes measuring biological activity of 0382. In another aspect, the invention features a method a GPCR polypeptide from the patient that is substantially of preventing or treating a disease of the breast including identical to a polypeptide listed in Table 1, wherein introducing into a human an expression vector that includes increased or decreased levels in the GPCR biological activ a nucleic acid molecule encoding a GPCR polypeptide ity, relative to normal levels, indicates that the patient has an substantially identical to a polypeptide listed in Table 1 increased risk for developing a disease or disorder of the operably linked to a promoter. bone and joints. 0383. In still another aspect, the invention features a 0380. In still another aspect, the invention features yet method of treating or preventing a disease of the breast another method for determining whether a patient has an including administering to an animal (e.g., a human) a increased risk for developing a disease or disorder of the compound that modulates the biological activity of a GPCR bone and joints. The method includes the step of measuring polypeptide Substantially identical to a polypeptide listed in the patient’s expression levels of a polypeptide listed in Table 1. Table 1, wherein altered levels in the expression, relative to 0384. In yet another aspect, the invention features a normal, indicate that the patient has an increased risk for method for determining whether a candidate compound is a developing a disease or disorder of the bone and joints. compound that may be useful for the treatment of a disease Preferably, the expression levels are determined by measur or disorder of the breast. This method includes the steps of ing levels of polypeptide or mRNA. (a) providing a GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR 0381 Diseases of the bone and joints that can be treated polypeptide with the candidate compound; and (c) measur or diagnosed using the methods of the invention or for which ing biological activity of the GPCR polypeptide, wherein candidate therapeutic compounds may be identified include altered biological activity, relative to that of the GPCR achondroplasia, acute bacterial arthritis, acute pyogenic polypeptide not contacted with the compound, indicates that osteomyelitis, Albright's syndrome, alkaptonuria (ochrono the candidate compound may be useful for the treatment of sis), aneurysmal bone cyst, ankylosing spondylitis, arthritic, a disease or disorder of the breast. The GPCR polypeptide arthropathies assocaited with hemoglobinopathies, arthropa can be in a cell or in a cell-free assay system. thy of acromegaly, arthropathy of hemochromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium 0385) In yet another aspect, the invention features a pyrophosphate deposition disease, chondrocalcinosis, chon method for determining whether a candidate compound is a droma, chondrosarcoma, choStochondritis, chrondromblas compound that may be useful for the treatment of a disease toma, congenital dislocation of the hip, congenital disorders or disorder of the breast. This method includes the steps of of joints, echondromatosis (dyschondroplasia, Ollier's dis (a) providing a transgenic non-human mammal (e.g., a ease), erosive osteoarthritis, Ewing's sarcoma, Felty’s Syn knock-out mouse) having a disruption in a nucleic acid drome, fibromyalgia, fibrous cortical defect, fibrous dyspla molecule encoding a GPCR polypeptide substantially iden sia (McCune-Albright syndrome, fungal arthritis, ganglion, tical to a polypeptide listed in Table 1; (b) contacting the giant cell tumor, gout, hematogenous osteomyelitis, hemo transgenic non-human mammal with the candidate com philic arthropathy, hereditary hyperphosphatasia, hyperos pound; and (c) measuring biological activity of the GPCR tosis, hyperostosis frontalis interna, hyperparathyroidism polypeptide in the transgenic non-human mammal, wherein (osteitis fibrosa cystica), hypertrophic osteoarthropathy, altered biological activity, relative to that of the transgenic infections diseases of joints, juvenile rheumatoid arthritis non-human mammal not contacted with the compound, (Still's disease), lyme disease, lymphoid neoplasms, indicates that the candidate compound may be useful for the melorheostosis, metabolic diseases of joints, metastatic car treatment of a disease or disorder of the breast. cinoma, metastatic neoplasms, monostatic fibrous dysplasia, 0386. In yet another aspect, the invention features a multiple exostoses (diaphyseal aclasis, osteochondromato method for determining whether a candidate compound is a sis), neoplasms, neuropathic joint (Charcot's joint), osteoar compound that may be useful for the treatment of a disease thritis, osteoarthrosis, osteoblastoma, osteochondroma or disorder of the breast. This method includes the steps of (exostosis), osteogenesis imperfecta (brittle bone disease), (a) providing a transgenic non-human mammal (e.g., a osteoid osteoma, osteoma, osteomalacia, osteomyelitis, mouse) overexpressing a nucleic acid molecule encoding a osteomyelosclerosis, osteopetrosis (marbel bone disease, GPCR polypeptide substantially identical to a polypeptide Albers-Schonberg disease), osteopoikilosis, osteoporosis listed in any one of Table 1; (b) contacting the transgenic (osteopenia), osteosarcoma, osteoscierosis, Paget’s disease non-human mammal with the candidate compound; and (c) of bone (osteitis deformans), parasitic arthritis, parosteal measuring biological activity of the GPCR polypeptide in osteosarcome, pigmented villonodular synovitis, polyostotic fibrous dysplasia, postinfectious or reactive arthritis, pro the transgenic non-human mammal, wherein altered biologi gressive diaphyseal dysplasia (Camurati-Engelmann dis cal activity, relative to that of the transgenic non-human ease), pseudogout, psoriatic arthritis, pyknodysostosis, pyo mammal not contacted with the compound, indicates that the genic arthritis, reflex sympathetic dystrophy syndrome, candidate compound may be useful for the treatment of a relapsing polychondritis, rheumatoid arthritis, rickets, senile disease or disorder of the breast. osteoporosis, sickle cell disease, spondyloepiphyseal dys 0387. In still another aspect, the invention features plasia, synovial chondromatosis, synovial sarcoma, syphi another method for determining whether a candidate com litic arthritis, talipes calcaneovalgus, talipes equinovarus, pound may be useful for the treatment of a disease or US 2006/0134109 A1 Jun. 22, 2006

disorder of the breast. This method includes (a) providing a normal levels, indicates that the patient has an increased risk nucleic acid molecule comprising a promoter from a gene for developing a disease or disorder of the breast. encoding a GPCR polypeptide listed in Table 1, the pro moter operably linked to a reporter system; (b) contacting 0394. In still another aspect, the invention features yet the nucleic acid molecule with the candidate compound; and another method for determining whether a patient has an (c) measuring reporter activity, wherein altered reporter increased risk for developing a disease or disorder of the activity, relative to a nucleic acid molecule not contacted breast. The method includes the step of measuring the with the compound, indicates that the candidate compound patient’s expression levels of a polypeptide listed in Table 1, may be useful for the treatment of a disease or disorder of wherein altered levels in the expression, relative to normal, the breast. indicate that the patient has an increased risk for developing a disease or disorder of the breast. Preferably, the expression 0388. In another aspect, the invention features yet levels are determined by measuring levels of polypeptide or another method for determining whether a candidate com mRNA. pound may be useful for the treatment of a disease or disorder of the breast. This method includes the steps of: (a) 0395 Diseases of the breast that can be treated or diag providing a GPCR polypeptide substantially identical to a nosed using the methods of the invention or for which polypeptide listed in Table 1; (b) contacting the polypeptide candidate therapeutic compounds may be identified include with the candidate compound; and (c) measuring interaction acute mastitis, breast abcess, carcinoma, chronic mastitis, of the candidate compound to the polypeptide. Interaction of congenital breast anomalies, cystic mastopathy, ductal car the compound to the polypeptide indicates that the candidate cinoma, ductal carcinoma in situ, ductal papilloma, fat compound may be useful for the treatment of a disease or necrosis, fibroadenoma, fibrocystic changes, fibrocystic dis disorder of the breast. ease, galactorrhea, granular cell tumor, gynecomastia, infil trating ductal carcinoma, inflammatory breast carcinoma, 0389. In still another aspect, the invention features inflammatory breast lesions, invasive lobular carcinoma, another method for determining whether a candidate com juvenile hypertrophy of the breast, lactating adenoma, lobu pound may be useful for the treatment of a disease or lar carcinoma in situ, neoplasms, Paget’s disease of the disorder of the breast. This method includes (a) providing a nipple, phyllodes tumor (cystosarcome phyllodes), polymas GPCR polypeptide substantially identical to a polypeptide tia, polymazia, polythelia, silicone granuloma, Supernumer listed in Table 1; (b) contacting the polypeptide with the ary breast, and Supernumerary nipples. candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the 0396. In another aspect, the invention features a method polypeptide, relative to that of the polypeptide not contacted of preventing or treating a disease of the immune system with the compound, indicates that the candidate compound including introducing into a human an expression vector that may be useful for the treatment of a disease or disorder of includes a nucleic acid molecule encoding a GPCR polypep the breast. Preferably the GPCR polypeptide is in a cell or tide substantially identical to a polypeptide listed in Table I a cell free assay system. operably linked to a promoter. 0390. In another aspect, the invention features a method 0397. In still another aspect, the invention features a for determining whether a patient has an increased risk for method of treating or preventing a disease of the immune developing a disease or disorder of the breast. The method system including administering to an animal (e.g., a human) includes the step of determining whether the patient has a a compound that modulates the biological activity of a mutation in a gene encoding a polypeptide listed in Table 1, GPCR polypeptide substantially identical to a polypeptide wherein presence of the mutation indicates that the patient listed in Table 1. has an increased risk for developing a disease or disorder of 0398. In yet another aspect, the invention features a the breast. method for determining whether a candidate compound is a 0391) In a related aspect, the invention features another compound that may be useful for the treatment of a disease method for determining whether a patient has an increased or disorder of the immune system. This method includes the risk for developing a disease or disorder of the breast. This steps of (a) providing a GPCR polypeptide substantially method includes the step of determining whether the patient identical to a polypeptide listed in Table 1; (b) contacting the has a polymorphism in a gene encoding a polypeptide listed GPCR polypeptide with the candidate compound; and (c) in Table 1, wherein presence of the polymorphism indicates measuring biological activity of the GPCR polypeptide, that the patient may have an increased risk for developing a wherein altered biological activity, relative to that of the disease or disorder of the breast. GPCR polypeptide not contacted with the compound, indi cates that the candidate compound may be useful for the 0392. In either of these two methods, the mutation or treatment of a disease or disorder of the immune system. The polymorphism is preferably associated with an alteration GPCR polypeptide can be in a cell or in a cell-free assay (for example, a decrease) in the biological activity of the system. polypeptide. 0399. In yet another aspect, the invention features a 0393. In another aspect, the invention features another method for determining whether a candidate compound is a method for determining whether a patient has an increased compound that may be useful for the treatment of a disease risk for developing a disease or disorder of the breast. The or disorder of the immune system. This method includes the method includes measuring biological activity of a GPCR steps of (a) providing a transgenic non-human mammal polypeptide from the patient that is substantially identical to (e.g., a knock-out mouse) having a disruption in a nucleic a polypeptide listed in Table 1, wherein increased or acid molecule encoding a GPCR polypeptide substantially decreased levels in the GPCR biological activity, relative to identical to a polypeptide listed in Table 1; (b) contacting the US 2006/0134109 A1 Jun. 22, 2006 42 transgenic non-human mammal with the candidate com method includes the step of determining whether the patient pound; and (c) measuring biological activity of the GPCR has a mutation in a gene encoding a polypeptide listed in polypeptide in the transgenic non-human mammal, wherein Table 1, wherein presence of the mutation indicates that the altered biological activity, relative to that of the transgenic patient has an increased risk for developing a disease or non-human mammal not contacted with the compound, disorder of the immune system. indicates that the candidate compound may be useful for the 0405. In a related aspect, the invention features another treatment of a disease or disorder of the immune system. method for determining whether a patient has an increased 0400. In yet another aspect, the invention features a risk for developing a disease or disorder of the immune method for determining whether a candidate compound is a system. This method includes the step of determining compound that may be useful for the treatment of a disease whether the patient has a polymorphism in a gene encoding or disorder of the immune system. This method includes the a polypeptide listed in Table 1, wherein presence of the steps of (a) providing a transgenic non-human mammal polymorphism indicates that the patient may have an (e.g., a mouse) overexpressing a nucleic acid molecule increased risk for developing a disease or disorder of the encoding a GPCR polypeptide substantially identical to a immune system. polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate com 0406. In either of these two methods, the mutation or pound; and (c) measuring biological activity of the GPCR polymorphism is preferably associated with an alteration polypeptide in the transgenic non-human mammal, wherein (for example, a decrease) in the biological activity of the altered biological activity, relative to that of the transgenic polypeptide. non-human mammal not contacted with the compound, 0407. In another aspect, the invention features another indicates that the candidate compound may be useful for the method for determining whether a patient has an increased treatment of a disease or disorder of the immune system. risk for developing a disease or disorder of the immune 04.01. In still another aspect, the invention features system. The method includes measuring biological activity another method for determining whether a candidate com of a GPCR polypeptide from the patient that is substantially pound may be useful for the treatment of a disease or identical to a polypeptide listed in Table 1, wherein disorder of the immune system. This method includes (a) increased or decreased levels in the GPCR biological activ providing a nucleic acid molecule comprising a promoter ity, relative to normal levels, indicates that the patient has an from a gene encoding a GPCR polypeptide listed in Table 1, increased risk for developing a disease or disorder of the the promoter operably linked to a reporter system; (b) immune System. contacting the nucleic acid molecule with the candidate 0408. In still another aspect, the invention features yet compound; and (c) measuring reporter activity, wherein another method for determining whether a patient has an altered reporter activity, relative to a nucleic acid molecule increased risk for developing a disease or disorder of the not contacted with the compound, indicates that the candi immune system. The method includes the step of measuring date compound may be useful for the treatment of a disease the patient’s expression levels of a polypeptide listed in or disorder of the immune system. Table 1, wherein altered levels in the expression, relative to 0402. In another aspect, the invention features yet normal, indicate that the patient has an increased risk for another method for determining whether a candidate com developing a disease or disorder of the immune system. pound may be useful for the treatment of a disease or Preferably, the expression levels are determined by measur disorder of the immune system. This method includes the ing levels of polypeptide or mRNA. steps of: (a) providing a GPCR polypeptide substantially 04.09 Diseases of the immune system that can be treated identical to a polypeptide listed in Table 1; (b) contacting the or diagnosed using the methods of the invention or for which polypeptide with the candidate compound; and (c) measur candidate therapeutic compounds may be identified include ing interaction of the candidate compound to the polypep abnormal neutrophil function, acquired immunodeficiency, tide. Interaction of the compound to the polypeptide indi acute rejection, Addison's disease, advanced cancer, aging, cates that the candidate compound may be useful for the allergic rhinitis, angioedema, arthrus-type hypersensitivity treatment of a disease or disorder of the immune system. reaction, ataxia-telangiectasia, autoimmune disorders, 0403. In still another aspect, the invention features autoimmune gastritis, autosomal recessive agammaglobu another method for determining whether a candidate com linemia, blood transfusion reactions, Bloom’s syndrome, pound may be useful for the treatment of a disease or Bruton's congenital agammaglobulinemia, bullous pem disorder of the immune system. This method includes (a) phigoid, Chédiak-Higashi syndrome, chronic active hepati providing a GPCR polypeptide substantially identical to a tis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immuno polypeptide listed in Table 1; (b) contacting the polypeptide deficiency, complement deficiency, congenital (primary) with the candidate compound; and (c) measuring the half immunodeficiency, contact dermatitis, deficiencies of life of the polypeptide, wherein an alteration in the half-life immune response, deficiency of the vascular response, der of the polypeptide, relative to that of the polypeptide not matomyositis, diabetes mellitus, disorders of microbial kill contacted with the compound, indicates that the candidate ing, disorders of phagocytosis, Goodpasture’s syndrome, compound may be useful for the treatment of a disease or graft rejection, graft-versus-host disease, granulocyt defi disorder of the immune system. Preferably the GPCR ciency, granulocytic leukemia, Graves' disease, Hashimo polypeptide is in a cell or a cell free assay system. to's thyroiditis, hemolytic anemia, hemolytic disease of the 0404 In another aspect, the invention features a method newborn, HIV infection (AIDS), Hodgkin’s disease, hyper for determining whether a patient has an increased risk for acute rejection, hyper-IgE syndrome, hypersensitivity pneu developing a disease or disorder of the immune system. The monitis, hypoparathyroidism, IgA deficiency, IgG subclass US 2006/0134109 A1 Jun. 22, 2006

deficiencies, immunodeficiency with thymoma, immunoglo bolic or nutritive disease or disorder. This method includes bulin deficiency syndromes, immunologic hypersensitivity, the steps of (a) providing a transgenic non-human mammal immunosupressive drug therapy, infertility, insulin-resistant (e.g., a knock-out mouse) having a disruption in a nucleic diabetes mellitus, interferon Y receptor deficiency, interleu acid molecule encoding a GPCR polypeptide substantially kin 12 receptor deficiency, iron deficiency, juvenile insulin identical to a polypeptide listed in Table 1; (b) contacting the dependent diabetes mellitus, Kaposi's sarcoma, lazy leu transgenic non-human mammal with the candidate com knock outcyte syndrom, localized type 1 hypersensitivity, pound; and (c) measuring biological activity of the GPCR lymphocytic leukemia, lymphoma, maignant B cell lym polypeptide in the transgenic non-human mammal, wherein phoma, major histocompatibility complex class 2 deficiency, altered biological activity, relative to that of the transgenic mixed connective tissue disease, mutliple myeloma, myas non-human mammal not contacted with the compound, thenia gravis, myeloperoxidase deficiency, neutropenia, indicates that the candidate compound may be useful for the nude syndrome, pemphigus Vulgaris, pernicious anemia, treatment of a metabolic or nutritive disease or disorder. postinfectious immunodeficiency, primary biliary cirrhosis, primary immunodeficiency, primary T cell immunodefi 0414. In yet another aspect, the invention features a ciency, progressive systemic sclerosis, protein-calorie mal method for determining whether a candidate compound is a nutrition, purine nucleoside phosphorylation deficiency, compound that may be useful for the treatment of a meta rheumatic fever, rheumatoid arthritis, secondary immuno bolic or nutritive disease or disorder. This method includes deficiency, selective (isolated) IgA deficiency, serum sick the steps of (a) providing a transgenic non-human mammal ness type hypersensitivity reaction, severe combined immu (e.g., a mouse) overexpressing a nucleic acid molecule nodeficiency, Sjögren's syndrome, sympathetic encoding a GPCR polypeptide substantially identical to a ophthalmitis, systemic lupus erythematosus, Systemic mas polypeptide listed in any one of Table 1; (b) contacting the tocytosis, Systemic type I hypersensitivity, T cell receptro transgenic non-human mammal with the candidate com deficiency, T lymphopenia (Nezelofs syndrome), thromb pound; and (c) measuring biological activity of the GPCR ocytopenia, thymic hypoplasia (DiGeorge syndrome), thy polypeptide in the transgenic non-human mammal, wherein mic neoplasms, thymoma (Goode’s syndrome), transient altered biological activity, relative to that of the transgenic hypogammaglobulinemia of infancy, type 1 (immediate) non-human mammal not contacted with the compound, hypersensitivity (atopy, anaphylaxis), type 2 hypersensitiv indicates that the candidate compound may be useful for the ity, type 3 hypersensitivity (immune complex injury), type 4 treatment of a metabolic or nutritive disease or disorder. (delayed) hyperSensitivity, urticaria, variable immunodefi 0415. In still another aspect, the invention features ciency, vitiligo, Wisknock Outtt-Aldrich syndrom, X-linked another method for determining whether a candidate com agammaglobulinemia, X-linked immunodeficiency with pound may be useful for the treatment of a metabolic or hyper IgM, X-linked lymphoproliferative syndrome, Zap70 nutritive disease or disorder. This method includes (a) pro tyrosine kinase deficiency. viding a nucleic acid molecule comprising a promoter from 0410. In another aspect, the invention features a method a gene encoding a GPCR polypeptide listed in Table 1, the of preventing or treating a metabolic or nutritive disease or promoter operably linked to a reporter system; (b) contact disorder, including introducing into a human an expression ing the nucleic acid molecule with the candidate compound; vector that includes a nucleic acid molecule encoding a and (c) measuring reporter activity, wherein altered reporter GPCR polypeptide substantially identical to a polypeptide activity, relative to a nucleic acid molecule not contacted listed in Table 1 operably linked to a promoter. with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive 0411. In still another aspect, the invention features a disease or disorder. method of treating or preventing a metabolic or nutritive disease or disorder, including administering to an animal 0416) In another aspect, the invention features yet (e.g., a human) a compound that modulates the biological another method for determining whether a candidate com activity of a GPCR polypeptide substantially identical to a pound may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes the steps polypeptide listed in Table 1. of: (a) providing a GPCR polypeptide substantially identical 0412. In yet another aspect, the invention features a to a polypeptide listed in Table 1; (b) contacting the polypep method for determining whether a candidate compound is a tide with the candidate compound; and (c) measuring inter compound that may be useful for the treatment of a meta action of the candidate compound to the polypeptide. Inter bolic or nutritive disease or disorder. This method includes action of the compound to the polypeptide indicates that the the steps of (a) providing a GPCR polypeptide substantially candidate compound may be useful for the treatment of a identical to a polypeptide listed in Table 1; (b) contacting the metabolic or nutritive disease or disorder. GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, 0417. In still another aspect, the invention features wherein altered biological activity, relative to that of the another method for determining whether a candidate com GPCR polypeptide not contacted with the compound, indi pound may be useful for the treatment of a metabolic or cates that the candidate compound may be useful for the nutritive disease or disorder. This method includes (a) pro treatment of a metabolic or nutritive disease or disorder. The viding a GPCR polypeptide substantially identical to a GPCR polypeptide can be in a cell or in a cell-free assay polypeptide listed in Table 1; (b) contacting the polypeptide system. with the candidate compound; and (c) measuring the half life of the polypeptide, wherein an alteration in the half-life 0413. In yet another aspect, the invention features a of the polypeptide, relative to that of the polypeptide not method for determining whether a candidate compound is a contacted with the compound, indicates that the candidate compound that may be useful for the treatment of a meta compound may be useful for the treatment of a metabolic or US 2006/0134109 A1 Jun. 22, 2006 44 nutritive disease or disorder. Preferably the GPCR polypep ciency, choline toxicity, chromium deficiency, chronic fat tide is in a cell or a cell free assay System. malabsorption, citrullinemia, classic branched-chain 0418. In another aspect, the invention features a method ketoaciduria, classic cystinuria, congenital chloridorrhea, for determining whether a patient has an increased risk for congenital erythropoietic porphyria, congenital generalized developing a metabolic or nutritive disease or disorder. The lipodystrophy, congenital myotonia, copper deficiency, cop method includes the step of determining whether the patient per toxicity, cyStathionine B-synthase deficiency, cys has a mutation in a gene encoding a polypeptide listed in tathioninuria, cystic fibrosis, cystinosis, cystinuria, Darier Table 1, wherein presence of the mutation indicates that the disease, defect in transport of long-chain fatty acids, defi patient has an increased risk for developing a metabolic or ciency of cobalamin coenzyme deficiency, Dent's Syn nutritive disease or disorder. drome, diatrophic dysplasia, dibasic aminoaciduria, dicar boxylic aminoaciduria, dihydropyrimidine dehydrogenase 0419. In a related aspect, the invention features another deficiency, distal renal tubular acidosis, dry beriberi, Dubin method for determining whether a patient has an increased Johnson syndrome, dysbetalipoproteinemia, end-organ risk for developing a metabolic or nutritive disease or insensitivity to Vitamin D. erythropoietic protoporphyria, disorder. This method includes the step of determining Fabry disease, failure of intestinal absorption, familial apo whether the patient has a polymorphism in a gene encoding protein C2 deficiency, familial combined hyperlipidemia, a polypeptide listed in Table 1, wherein presence of the familial defective Apo B100, familial goiter, familial hyper polymorphism indicates that the patient may have an cholesterolemia, familial hypertriglyceridemia, familial increased risk for developing a metabolic or nutritive disease hypophosphatemic rickets, familial lipoprotein lipase defi or disorder. ciency, familial partial lipodystrophy, Fanconi-Bickel Syn 0420. In either of these two methods, the mutation or drome, fluoride deficiency, folate malabsorption, folic adic polymorphism is preferably associated with an alteration deficiency, formiminoglutamic aciduria, fructose 1.6 (for example, a decrease) in the biological activity of the diphosphatase deficiency, galactokinase deficiency, galac polypeptide. tose 1-phosphate uridyl transferase deficiency galactosemia, Gaucher disease, Gitelman's syndrone, globoid cell leu 0421. In another aspect, the invention features another knock outdystrophy, glucose-6-phosphatease deficiency, method for determining whether a patient has an increased glucose-6-translocase deficiency, glucose-galactose malab risk for developing a metabolic or nutritive disease or Sorption, glucose-tranporter protein syndrome, glutaric adi disorder. The method includes measuring biological activity duria, glycogen storage disease type 2, glycogen storage of a GPCR polypeptide from the patient that is substantially disease type Ib, glycogen storage disease type ID, glycogen identical to a polypeptide listed in Table 1, wherein synthase deficiency, gout, Hartnup disease, hawkinsinuria, increased or decreased levels in the GPCR biological activ hemochromatosis, hepatic glycogenosis with renal fanconi ity, relative to normal levels, indicates that the patient has an syndrome, hepatic lipase deficiency, hepatic porphyria, increased risk for developing a metabolic or nutritive disease hereditary coproporphyria, hereditary fructose intolerance, or disorder. hereditary Xanthinuria, Hers disease, histidinemia, histidi nuria, HIV-1 protease inhibitor-induced lipodystrophy, 0422. In still another aspect, the invention features yet homocitrullinuria, homocystinuria, homocystinuria, another method for determining whether a patient has an homocystinuria and methylmalonic acidemia, homocysti increased risk for developing a metabolic or nutritive disease nurias, Hunter syndrome, Hurler disease, Hurler-Scheie dis or disorder. The method includes the step of measuring the ease, hyophosphatemic rickets, hyperammonemia, hyper patient’s expression levels of a polypeptide listed in Table 1, ammonemia, hypercholesterolemia, hypercystinuria, wherein altered levels in the expression, relative to normal, hyperglycinemia, hyperhydroxyprolinemia, hyperkalemic indicate that the patient has an increased risk for developing periodic paralysis, hyperleucineisoleucinemia, hyperlipo a metabolic or nutritive disease or disorder. Preferably, the proteinemias, hyperlysinemia, hypermagnesemia, hyperme expression levels are determined by measuring levels of tabolism, hypermethioninemia, hyperomithinemia, hyper polypeptide or mRNA. oxaluria, hyperphenylalaninemia with primapterinuria, 0423 Preferred metabolic or nutritive diseases and dis hyperphenylalaninemias, hyperphosphatemia, hyperproline orders that can be treated or diagnosed using the methods of mia, hypertriglyceridemia, hyperuricemia, hypervalinemia, the invention or for which candidate therapeutic compounds hypervitaminosis A, hypervitaminosis D, hypocholester may be identified include 5,10-methylenetetrahydrofolate olemia, hypometabolism, hypophosphatemia, hypourice reductase deficiency, achondrogenesis type 1B, acid C.-1.4 mia, hypovitaminosis A, hypoxanthine phosphoribosyltrans glucosidase deficiency, acquired generalized lipodystrophy ferase deficiency, iminoglycinuria, iminopeptiduria, (Lawrence syndrome), acuired partial lipodystrophy (Bar intermittent branched-chain ketoaciduria, intestinal malab raquer-Simons syndrome), acute intermittent porphyria, Sorption, iodine deficiency, iron deficiency, isovaleric aci acute panniculitis, adenine phosphoribosyltransferase defi demia, Jervell and Lange-Nielsen syndrome, juvenile per ciency, adenosine deaminase deficiency, adenyloSuccinate nicious anemia, keshan disease, Knock outrsaknock outffs lyase deficiency, adiposis dolorosa (Dercum disease), ALA syndrome, kwashiorknock outr, leuknock outdystrophies, dehydratase-deficient porphyria, albinism, alkaptonuria, Liddle's syndrome, lipodystrophies, lipomatosis, liver gly amulopectinosis, Andersen disease, argininemia, arginino cogenoses, liver phosphorylase kinase deficiency, long QT Succinic aciduria, astelosteogenesis type 2, Bartter's Syn syndrome, lysinuria, lysosomal storage diseases, magne drome, benign familial neonatal epilepsy, benign fructo sium deficiency, malabsorptive diseases, malignant hyper Suria, benign recurrent and progressive familial intrahepatic phenylalaninemia, manganese deficiency, marasmus, Maro cholestasis, biotin deficiency, branching enzyme deficiency, teaux-Lamy disease, McArdle disease, Menkes' disease, calcium deficiency, carnitine transport defect, choline defi metachromatic leuknock outdystrophy, methionine malab US 2006/0134109 A1 Jun. 22, 2006

Sorption, methylmalonic acidemia, molybdenum deficiency, the steps of administering a candidate compound to a monosodiumurate gout, Morquio syndrome, mucolipidoses, transgenic mouse expressing a transgene encoding a GPCR mucopolysaccharidoses, multiple carboxylase deficiency polypeptide listed in Table 1; and determining whether the syndrome, multiple symmetric lipomatosis (Madelung dis candidate compound decreases the biological activity of the ease, muscle glycogenoses, muscle phosphofructokinase GPCR polypeptide, wherein a decrease in the biological deficiency, muscle phosphorylase deficiency, myoadenylate activity of the GPCR polypeptide identifies the candidate deaminase deficiency, nephrogenic diabetes insipidus, compound as a compound that may be useful for the nesidioblastosis of pancreas, niacin deficiency, niacintox treatment of a disease or disorder. In one embodiment, the icity, Niemann-Pick disease, obesity, orotic aciduria, osteo transgenic mouse has a mutation (e.g., a deletion, frameshift, malacia, paramyotonia congenita, pelagra, Pendred syn insertion or a point mutation) in a gene listed in Table 1. In drome, phenylketonuria, phenylketonuria type 1, a related embodiment, the mouse has a mutation in the gene phenylketonuria type 2, phenylketonuria type 3. phosphate that is orthologous to the transgene. deficiency, phosphoribosylpyrophosphate synthetase over activity, polygenic hypercholesterolemia, Pompe disease, 0428. In a related aspect, the invention features another porphynia cutanea tarda, porphyrias, primary bile acid mal method for identifying a compound that may be useful for absorption, primary hyperoxaluria, primary hypoalphalipo the treatment of a disease or disorder described herein. This proteinemia, propionic acidemia, protein-energy malnutri method includes the steps of administering a candidate tion, proximal renal tubular acidosis, purine nucleoside compound to a transgenic mouse expressing a transgene phosphorylase deficiency, pyridoxine deficiency, pyrimidine encoding a GPCR polypeptide in a gene listed in Table 1, 5'-nucleotidase deficiency, renal glycosuria, riboflavin defi and having a disease or disorder caused by the expression of ciency, rickets, Rogers’ syndrome, Saccharopinuria, Sand the transgene; and determining whether the candidate com hoff disease, Sanfilippo syndromes, sarcosinemia, Scheie pound treats the disease or disorder. disease, Scurvy (vitamin C deficiency), selenium deficiency, 0429. In a related aspect, the invention features another Selenosis, sialic acid storage disease, S-Sulfo-L-cysteine, method for identifying a compound that may be useful for Sulfite, thiosulfaturia, Tarui disease, Tay-Sachs disease, thia the treatment of a disease or disorder described herein. This mine deficiency, tryptophan malabsorption, tryptophanuria, method includes the steps of administering a candidate type I pseudohypoaldosteronism, type 3 glycogen storage compound to a transgenic mouse transgenic mouse contain disease (debrancher deficiency, limit dextrinosis), tyrosine ing a mutation (e.g., a deletion, frameshift, insertion or a mia, tyrosinemia type 1, tyrosinemia type 2, tyrosinemia point mutation) in a gene listed in Table 1, and having a type 3, uridine diphosphate galactose 4-epimerase defi disease or disorder caused by gene disruption; and deter ciency, urocanic aciduria, variegate porphyria, Vitamin B12 mining whether candidate compound treats the disease or deficiency, vitamin C toxicity, Vitamin D deficiency, vitamin disorder. D-resistant rickets, vitamin d-sensitive rickets, vitamin E 0430. In still another aspect, the invention features a deficiency, vitamin E toxicity, Vitamin K deficiency, vitamin method for identifying a compound that may be useful for K toxicity, von Gierke disease, Wernicke's encephalopathy, the treatment of a disease or disorder described herein. This wet beriberi, Wilson's disease, Xanthurenic aciduria, method includes the steps of contacting a candidate com X-linked sideroblastic anemia, Zinc deficiency, Zinc toxicity, pound with a cell from a transgenic mouse expressing a C.-ketoadipic aciduria, C.-methylacetoacetic aciduria, B-hy transgene encoding a GPCR polypeptide in a gene listed in droxy-3-methylglutaric aciduria, B-methylcrotonyl glyci Table 1; and determining whether the candidate compound la decreases the biological activity of the GPCR polypeptide. 0424. In another aspect, the invention features a trans A decrease in the biological activity of the GPCR polypep genic mouse expressing a transgene encoding a human tide identifies the candidate compound as a compound that GPCR polypeptide listed in Table 1. The transgene may be may be useful for the treatment of a disease or disorder. In operably linked, e.g., to an inducible, cell-type, or tissue one embodiment, the transgenic mouse from which the cell specific promoter. In one embodiment, the transgenic mouse was derived has a mutation (e.g., a deletion, frameshift, has a mutation in a gene that is orthologous to the transgene. insertion or a point mutation) in a gene listed in Table 1. In For example, the transgene encoding the human GPCR a related embodiment, the mouse has a mutation in the polypeptide may entirely replace the coding sequence of the polypeptide that is orthologous to the GPCR polypeptide orthologous mouse gene or the transgene might complement encoded by the transgene. a knock out of the orthologous mouse gene. 0431. The invention also features a kit that includes a 0425. In a related embodiment, the transgenic mouse has plurality of polynucleotides, wherein each polynucleotide a mutation (e.g., a deletion, frameshift, insertion or a point hybridizes under high stringency conditions to a GPCR mutation) in a gene listed in Table 1. polynucleotide of Table 1. At least 50 different polynucle otides, each capable of hybridizing under high Stringency 0426 In another aspect, the invention features an isolated conditions to a different huma GPCR polynucleotide listed cell or population of cells derived from a transgenic mouse on Table 1, are present in the kit. either expressing a transgene encoding a huma GPCR polypeptide listed in Table 1 or has a mutation (e.g., a 0432. The invention features another kit that includes a deletion, frameshift, insertion or a point mutation) in a gene plurality of polynucleotides. In this kit, polynucleotides that listed in Table 1. hybridize under high Stringency conditions, each to a dif ferent GPCR polynucleotide listed on one of Tables 3-33, 0427. The invention also features a method for identify are present in the kit Such that the kit includes polynucle ing a compound that may be useful for the treatment of a otides that collectively hybridize to every GPCR polynucle disease or disorder described herein. The method includes otide listed on one of Tables 3-33. US 2006/0134109 A1 Jun. 22, 2006 46

0433. The invention features another kit, this kit includ 99%, by weight, pure. A substantially pure GPCR polypep ing a plurality of mice, each mouse having a mutation in a tide may be obtained, for example, by extraction from a GPCR polynucleotide of Table 1, wherein at least 50 mice, natural source (e.g., a pancreatic cell), by expression of a each having a mutation in a different GPCR polynucleotide recombinant nucleic acid encoding a GPCR polypeptide, or listed on Table 1, are present in the kit. This kit may by chemically synthesizing the polypeptide. Purity can be optionally include a plurality of polynucleotides, wherein measured by any appropriate method, e.g., by column chro each polynucleotide hybridizes under high Stringency con matography, polyacrylamide gel electrophoresis, or HPLC ditions to a GPCR polynucleotide of Table 1, wherein at analysis. least 50 different polynucleotides, each capable of hybrid izing under high Stringency conditions to a different mouse 0441. A polypeptide is substantially free of naturally GPCR polynucleotide listed on Table 1, are present in the associated components when it is separated from those kit. contaminants that accompany it in its natural State. Thus, a polypeptide which is chemically synthesized or produced in 0434. The invention features another kit that includes a a cellular system different from the cell from which it plurality of mice having a mutation in a GPCR polynucle naturally originates will be substantially free from its natu otide. In this kit, mice having a mutation in each GPCR rally associated components. Accordingly, Substantially pure polynucleotide listed on one of Tables 3-33 are present in the polypeptides include those that naturally occur in eukaryotic kit. organisms but are synthesized in E. coli, yeast or other 0435. In any of the foregoing kits, at least one of the microbial system. GPCR polynucleotides is desirably a GPCR polynucleotide 0442. By “purified antibody' is meant antibody that is at of Table 2. least 60%, by weight, free from proteins and naturally occurring organic molecules with which it is naturally DEFINITIONS associated. Preferably, the preparation is at least 75%, more 0436 By “polypeptide' is meant any chain of more than preferably 90%, and most preferably at least 99%, by two amino acids, regardless of post-translational modifica weight, antibody. A purified antibody may be obtained, for tion Such as glycosylation or phosphorylation. example, by affinity chromatography using recombinantly produced protein or conserved motif peptides and standard 0437. By “substantially identical' is meant a polypeptide techniques. or nucleic acid exhibiting at least 50%, preferably 85%, more preferably 90%, and most preferably 95% identity to 0443 By “specifically binds' is meant any small mol a reference amino acid or nucleic acid sequence. For ecule, peptide, antibody, or polypeptide that recognizes and polypeptides, the length of comparison sequences will gen binds, for example, a huma GPCR polypeptide but does not erally be at least 16 amino acids, preferably at least 20 amino Substantially recognize and bind other molecules in a acids, more preferably at least 25 amino acids, and most sample, e.g., a biological sample, that naturally includes the preferably 35 amino acids or the full-length polypeptide. For protein. nucleic acids, the length of comparison sequences will generally be at least 50 nucleotides, preferably at least 60 0444. By “polymorphism' is meant that a nucleotide or nucleotides, more preferably at least 75 nucleotides, and nucleotide region is characterized as occurring in several most preferably 110 nucleotides or the full-length poly different sequence forms. A "mutation' is a form of a nucleotide. polymorphism in which the expression level, stability, func tion, or biological activity of the encoded protein is Sub 0438 Sequence identity is typically measured using a stantially altered. sequence analysis program (e.g., BLAST 2: Tatusova et al., FEMS Microbiol Lett. 174:247-250, 1999) with the default 0445. By “GPCR related polypeptide' is meant a parameters specified therein. polypeptide having Substantial identity to any of the polypeptides listed in Table 1, including polymorphic forms 0439. By “high stringency conditions” is meant hybrid (e.g., sequences having one or more SNPs) and splice ization in 2xSSC at 40°C. with a DNA probe length of at variants. least 40 nucleotides. For other definitions of high stringency conditions, see F. Ausubel et al., Current Protocols in 0446. By “GPCR biological activity” is meant measur Molecular Biology, pp. 6.3.1-6.3.6. John Wiley & Sons, able effect or change in an organism or a cell resulting from New York, N.Y., 1994, hereby incorporated by reference. the modulation of a GPCR at the molecular, cellular, physi “Substantially identical polynucleotides also include those ological or behavioral levels or alteration in the extent of that hybridize under high stringency conditions. “Substan activation or deactivation that can be elicited by an agonist tially identical polypeptides include those encoded by or antagonist. polynucleotides that hybridize under high Stringency con ditions. 0447) “Dominant negative” means an effect of a mutant form of a gene product that dominately interferes with the 0440 By “substantially pure polypeptide' is meant a function of the normal gene product. polypeptide that has been separated from the components that naturally accompany it. Typically, the polypeptide is 0448 “Reporter system” means any gene, compound or substantially pure when it is at least 60%, by weight, free polypeptide whose product can be assayed, measured or from the proteins and naturally-occurring organic molecules monitored. Examples include, but are not limited to neomy with which it is naturally associated. Preferably, the cin (Kang et al., Mol. Cells: 7:502-508, 1997), luciferase polypeptide is a GPCR polypeptide that is at least 75%, (Welsh et al., Curr. Opin. Biotechnol. 8:617-622, 1997), lacz, more preferably at least 90%, and most preferably at least (Spergel et al., Prog. Neurobiol. 63:673-686, 2001), US 2006/0134109 A1 Jun. 22, 2006 47 aequorin (Deo et al., J. Anal. Chem. 369:258-266, 2001) and 0454) “Allele" refers to one of two or more alternative green fluorescent protein (Tsien, Annu. Rev. Biochem. forms of a gene occurring at a given locus in the genome. 67:509-544, 1998). 0455. A “transgenic organism,” as used herein, is any 0449) “Conditional mutant” is any gene, cell or organism organism, including but not limited to animals and plants, in for which the expression of the mutant phenotype can be which one or more of the cells of the organism contains controlled through alteration in the temperature, diet or other heterologous nucleic acid introduced by way of human external conditions. intervention, Such as by transgenic techniques well known in 0450 “Overexpression” means level of expression higher the art. The nucleic acid is introduced into the cell, directly than the physiological level of expression. or indirectly by introduction into a precursor of the cell, by 0451) “Isolated” or “purified” means altered from its way of deliberate genetic manipulation, Such as by micro natural state, i.e., if it occurs in nature, it has been changed injection, transfection or by infection with a recombinant or removed from its original environment, or both. For virus. The transgenic organisms contemplated in accordance example, a polynucleotide or a polypeptide naturally present with the present invention include mice, bacteria, cyanobac in a living organism is not "isolated.” but the same poly teria, fungi, plants and animals. The isolated DNA of the nucleotide or polypeptide separated from the coexisting present invention can be introduced into the host by methods materials of its natural state is "isolated,” as the term is known in the art, for example infection, transfection, trans employed herein. Moreover, a polynucleotide or polypeptide formation or transconjugation. that is introduced into an organism by transformation, 0456. A “transgenic mice,” as used herein, is a mouse, in genetic manipulation, or by any other recombinant method which one or more of the cells of the organism contains is "isolated even if it is still present in the organism. nucleic acid introduced by way of human intervention, such 0452 “Polynucleotide’ generally refers to any polyribo as by transgenic techniques well known in the art. The nucleotide (RNA) or polydeoxribonucleotide (DNA), which nucleic acid is introduced into the cell, directly or indirectly may be unmodified or modified RNA or DNA. Polynucle by introduction into a precursor of the cell, by way of otides include, without limitation, single- and double deliberate genetic manipulation, by methods known in the stranded DNA, DNA that is a mixture of single- and art, for example microinjection, infection, transfection, or double-stranded regions, single- and double-stranded RNA, transformation. and RNA that is mixture of single- and double-stranded 0457) “Transgene' is any exogenously added nucleic regions, hybrid molecules comprising DNA and RNA that acid. may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. Poly 0458 “Antisense' or “Reverse complement’ means a nucleotide can also refer to triple helix nucleic acids. nucleic acid sequence complementary to the messenger 0453 “Variant” refers to a polynucleotide or polypeptide RNA. that differs from a reference polynucleotide or polypeptide, 0459) “Single nucleotide polymorphism” or “SNP” refers but retains the essential properties thereof. A typical variant to the occurrence of nucleotide variability at a single nucle of a polynucleotide differs in nucleotide sequence from the otide position in the genome, within a population. An SNP reference polynucleotide. Changes in the nucleotide may occur within a gene or within intergenic regions of the sequence of the variant may or may not alter the amino acid genome. SNPs can be assayed using Allele Specific Ampli sequence of a polypeptide encoded by the reference poly fication (ASA). For this process, at least three primers are nucleotide. Nucleotide changes may result in amino acid required. A common primer is used in reverse complement Substitutions, additions, deletions, fusions and truncations in to the polymorphism being assayed. This common primer the polypeptide encoded by the reference sequence, as can be between 50 and 1500 bps from the polymorphic base. discussed below. A typical variant of a polypeptide differs in The other two (or more) primers are identical to each other amino acid sequence from the reference polypeptide. Gen except that the final 3' base wobbles to match one of the two erally, alterations are limited so that the sequences of the (or more) alleles that make up the polymorphism. Two (or reference polypeptide and the variant are closely similar more) PCR reactions are then conducted on sample DNA, overall and, in many regions, identical. A variant and ref each using the common primer and one of the Allele Specific erence polypeptide may differ in amino acid sequence by Primers. one or more substitutions, insertions, or deletions in any combination. A Substituted or inserted amino acid residue 0460 “Splice variant” as used herein refers to cDNA may or may not be one encoded by the genetic code. Typical molecules produced from RNA molecules initially tran conservative substitutions include Gly, Ala; Val, Ile, Leu: scribed from the same genomic DNA sequence but which Asp, Glu: Asn., Gln: Ser. Thr; Lys, Arg; and Phe and Tyr. A have undergone alternative RNA splicing. Alternative RNA variant of a polynucleotide or polypeptide may be naturally splicing occurs when a primary RNA transcript undergoes occurring Such as an allele, or it may be a variant that is not splicing, generally for the removal of introns, which results known to occur naturally. Non-naturally occurring variants in the production of more than one distinct mRNA mol of polynucleotides and polypeptides may be made by ecules each of which may encode different amino acid mutagenesis techniques or by direct synthesis. Also included sequences. The term splice variant also refers to the as variants are polypeptides having one or more post polypeptides encoded by the above mRNA molecules. translational modifications, for instance glycosylation, phos 0461) “Fusion protein’ refers to a polypeptide encoded phorylation, methylation, ADP ribosylation and the like. by two, often unrelated, fused genes or fragments thereof. Embodiments include methylation of the N-terminal amino acid, phosphorylations of serines and threonines and modi 0462 By “candidate compound' or “test compound is fication of C-terminal glycines. meant a chemical, be it naturally-occurring or artificially US 2006/0134109 A1 Jun. 22, 2006 48 derived, that is assayed for its ability to modulate gene 0469 FIG. 4 is schematic summary of tissue expression activity or protein stability or binding, expression levels, or in 100 GPCR polynucleotides. Polynucleotides were ana activity, by employing any standard assay method. Test lyzed individually by RT-PCR, as shown in FIG. 3, and the compounds may include, for example, peptides, polypep intensity of the observed bands determined by Scanning. tides, synthesized organic molecules, naturally occurring Each gene is represented by a single row of colored boxes, organic molecules, polynucleotide molecules, and compo with four different expression levels: no expression blue; nents thereof. low expression purple; moderate expression—dark red; 0463. By “promoter' is meant a minimal sequence suf strong expression pure red. Polynucleotides and tissues, as ficient to direct transcription. Also included in the invention well as groups of expression patterns, are indicated. are those promoter elements which are sufficient to render 0470 FIGS. 5a-5h are representative in situ hybridiza promoter-dependent gene expression controllable for cell tion photomicrographs of GPCR expression in the mouse type-specific, tissue-specific, temporal-specific, or inducible brain. FIG. 5a: GPR63 in the Ammons horn (CA) regions of by external signals or agents; such elements may be located the hippocampus. FIG.5b. PGR7 in the habenula. FIG.5c. in the 5' or 3' or intron sequence regions of the native gene. GRCA in the cortex and thalamus. FIG. 5d. GPR63 in the Purkinje cells of the cerebellum. FIG. 5e: GPR37 in the 0464 By “operably linked' is meant that a gene and one frontal cortex. FIG. 5f GPR26 in the inferior olive. FIG. or more regulatory sequences are connected in Such a way 5g. GPR50 in the cells lining the third ventricle. FIG. 5h. as to permit gene expression. PGR15 in the preoptic region of the hypothalamus. Vertical 0465. Other features and advantages of the invention will lines on Sagittal mouse brain drawing represent approximate be apparent from the following description of the preferred coronal plane of photomicrographs. Scale bars=500 um. embodiments thereof and from the claims. 0471 FIGS. 6a-6b. Home Cage Activity data for GPR85. FIG. 6A. illustrates the average 24 hour activity of GPR85 BRIEF DESCRIPTION OF THE DRAWINGS wild type and knock out female mice. FIG. 6B illustrates the 0466 FIG. 1 is a list of GPCR polynucleotides of the average 24 hour activity of GPR85 wild type and knockout invention in human and mouse. Polynucleotides are divided male mice. into four classes, A, B, C, and F/S, according to conventional 0472 FIGS. 7a-7b. Temperature differences between classification of the GPCR superfamily. The “No Class” GPR85 knockout and wild type mice. FIG. 7A. SIH results group includes five polynucleotides that cannot be assigned showing an increased body temperature change for knock to any of the above four classes. Within each class, poly out compared to wild type mice. FIG. 7B. Baseline core nucleotides are further grouped into Small families based on body temperature difference between wild type and knock ligand specificity or, in the case of orphan receptors, sig out mice. nificant sequence homology (24.0%) within each family. Orphan receptors that cannot be grouped by this criterion are 0473 FIG. 8. Percentage freezing in the conditioned fear alphabetically listed at the end of each class. Whenever test. GPR85 knock out mice displayed significantly more available, names are adopted from the official gene names of freezing responses during the context test. the NCBI LocusLink database. Orphan GPCRs are indicated 0474 FIGS. 9a-9b. Acute effects of ethanol-induced with an asterisk. Abbreviations: H, human; M, mouse; hypothermia. FIG.9A. Initial sensitivity to the hypothermic FMLP, fMet-Leu-Phe: GNRH; gonadotropin-releasing hor effects of ethanol as measured by the difference before and mone: PAF, platelet-activating factor: INSL3, insulin-like 3: 30 minutes after an ip injection of 2.5 g/kg ethanol on two SPC, sphingosylphosphorylcholine; LPC, lysophosphatidyl consecutive treatment days. GPR85 knock out mice display choline; TRH, thyrotropin-releasing hormone: LGR, leu a decreased initial sensitivity to the effects of ethanol. FIG. cine-rich repeat-containing G protein-coupled receptor, 9B. Tolerance to the hypothermic effects of ethanol as shown SREB, super conserved receptor expressed in brain; GIP, by the difference in the change of core body temperature for gastric inhibitory polypeptide; GHRH, growild typeh hor day 1 and day 2. mone-releasing hormone: PACAP pituitary adenylate cyclase activating polypeptide; DAF, decay accelerating DETAILED DESCRIPTION OF THE factor; GPRC5, G protein-coupled receptor family C group INVENTION 5. 0467 FIG. 2 is a series of phylogenetic trees of human 0475 G protein coupled receptors (GPCRs) include GPCRs. Lines corresponding to individual polynucleotides receptors for neurotransmitters, light, odors, hormones, and are colored black for those with known ligands, red for molecules used for communication in the immune system. orphan genes, and blue for genes with 7 trans-membrane GPCRs are by far the largest family of receptors known. It domains but no homology to known GPCRs. The Class A is believed that there are as many as 1,000 different GPCRs tree was split into two parts due to size considerations (arrow for odor recognition alone. line indicates the connection). Families are defined as Identification of GPCR Polypeptides and Polynucleotides described in FIG. 1. Clusters of GPCRs with significant predictive value as to ligands are highlighted in purple on 0476) To identify the full complement of GPCRs in these bootstrap consensus trees (bootstrap values not human and mouse, we embarked on a multi-step process; the shown). The ruler at the bottom of each tree indicates the first step was to identify previously known GPCR genes and horizontal distance equal to 10% sequence divergence. then the subsequent identification of novel genes. To identify known genes we searched the public literature and sequence 0468 FIG. 3 is a photograph showing the expression databases of the National Center for Biotechnolgy Informa profiles of nine GPCRs as identified by RT-PCR. tion for human and mouse GPCRs and then performed US 2006/0134109 A1 Jun. 22, 2006 49 sequence comparisons. This procedure defined a unique database (downloaded in August, 2001) using TBLASTN at gene set of GPCRs for both human and mouse and identified an E-value of 10. The resulting hits (-500,000) were com the human and mouse orthologs. In total, 340 GPCRs were bined and Sorted according to contig and position numbers. identified in human and 304 in mouse. Sequence alignments Only the hit with the best E-value was selected among the indicated that 260 of these molecules were common to both group of hits within 1kb from each other on the same contig. species (FIG. 1). Each of the ~50,000 unique hits generated were used to search against nr protein database using BLASTP. From this 0477 We then asked whether the remaining GPCR genes search, 10,000 hits appeared to be most homologous to (80 human and 44 in mouse), which did not show a GPCRs. Almost 2000 of these hits were determined to be counterpart in the other species, might have undiscovered parts of various known GPCRs and were excluded from orthologs. Using the non-shared GPCRs as queries, the further consideration. The best 500 of the remaining hits public human and mouse genome sequence databases were were subjected to full-length gene structure prediction. This searched for orthologous genes using TBLASTN, a varia process involved comparison of 200 kb genomic DNA tion of the Basic Local Alignment Search Tool (BLAST). sequence Surrounding each hit with the full-length sequence These studies identified mouse orthologs for 61 of the of its most homologous known GPCR using BLAST2. human GPCRs, but no orthologs could be found for the Twenty-five candidate novel GPCRs were obtained. Their remaining 19 (FIG. 1). No human orthologs were detected nucleotide sequences were then used to search the EST for 43 of the mouse genes. Thirty-three of these mouse genes database for the identification of human and/or mouse ESTs. belonged to the trace amine and MAS-related gene families. In combination with the literature/database searches, these 0482 For the HMM profile-based approach, GPCR Class studies for orthologs increased the number of GPCRs to 342 A, B and C HMM models were downloaded from the Pfam in human and 366 in mouse, with 323 GPCRs shared by the database and were used as queries in the HMMSEARCH two species (FIG. 1). program (HMMER package) to search against the Interna tional Protein Index (IPI) proteome database. All hits with 0478 We subsequently undertook an exhaustive search E-values of less than 0.01 were evaluated for the existence for new human GPCR genes. Two different approaches were of 7TM domains using the HMMTOP program. Full-length used. In the first, we employed a homology-based strategy to coding sequences were predicted through a combination of search the human genome sequence database for genes methods including EST sequence assembly, ORF Finder, encoding GPCRs (http://genome.ucsc.edu/goldenPath/ GenomeScan, GeneWise and GeneScan programs. 14nov2002/chromosomes/). Two hundred fifty-four known GPCRs, representative of all classes, were each used as an 0483 GPCRs from the same class were aligned to the independent query in TBLASTN searches of all human class specific HMM model using the HMMALIGN program chromosomes. These searches yielded ~500,000 matches, of the HMMER package. Positions not aligned to matching which were first reduced to ~50,000 unique matches and sites in the HMM model were removed. These multiple then to 10,000 matches with homology to known GPCRs alignments were used to build neighbor-joining phyloge (see Methods). Among these, hits representing 315 of the netic trees by the ClustalW program. Gaps and multiple 342 known GPCR genes were detected, consistent with Substitutions were not corrected. Bootstrap consensus trees 90%-95% coverage of the human genome database. were plotted using TreeView. They were rooted using Approximately 1000 hits were homologous to chemosen GPCRs that did not fit into any of four known classes. sory GPCR receptors. Continued analysis of the remaining Bootstrap values for nodes near the root of the Class A tree hits revealed 25 novel GPCR genes. were very low (<10%), reflecting the distant homology of the different families in this class. 0479. In a second discovery method, a search was con ducted for proteins with sequence motifs characteristic of Phylogenetic Analysis the four different classes of GPCRs. The Hidden Markov 0484 Phylogenetic and receptor-ligand relationships Model (HMM) profile-based approach was used to search among the GPCRs were subsequently analyzed. Each the human proteome. This method yielded 1,100 potential human and mouse GPCR was first assigned to one of the matches. Among these hits 331 of the 342 known GPCRs four distinct classes of GPCRs (A, B, C, F/S) by comparing were represented, confirming the validity of the search with HMM models. All but five of the receptors (TPRA40, strategy. Following elimination of known genes, three novel TM7SFI, TM7SFILI, TM7SFIL2 and TM7SF3) could be genes were identified. The combination of both genomic assigned to one of the four classes by this method. These search strategies revealed 28 GPCR genes that have not been assignments indicate that of 370 human GPCRs. 287 belong previously described. These genes are referred to as PGRI to to Class A, 50 to Class B, 17 to Class C, and 11 to Class F/S. PGR28 (FIG. 1). Searches of the mouse genome sequence Of 393 mouse GPCRs, 311, 50, 17, and 10 belong to Classes database, together with RT-PCR analyses, identified A, B, C, and F/S, respectively. orthologs for 25 of the 28 novel genes in the mouse. 0485 The GPCRs were next catalogued according to 0480. Altogether, these searches identified a total of 383 ligand specificities reported in the literature. This effort GPCRs in human and 391 in mouse; 358 of the GPCRs were identified 229 human and 215 mouse GPCRs with known common to the two species. ligands. The remaining 145 human and 178 mouse GPCRs have no known ligands and are therefore orphan receptors. Methods Among the orphan receptors, 100 human and 133 mouse 0481. The 254 GPCRs used as queries were aligned using receptors belong to Class A, 34 human and 34 mouse the Clustal W program. The amino acid sequence of the receptors to Class B, 6 human and 6 mouse receptors to seven-transmembrane region of each GPCR was extracted Class C, none to Class F/S, and 5 human and 5 mouse and used to search through the public human genome (HG) receptors could not be assigned to a specific class (FIG. 1). US 2006/0134109 A1 Jun. 22, 2006 50

0486) The GPCRs were subsequently divided into a Full-Length Sequence for Novel Human GPCR Genes series of families of related receptors that either recognize Methods the same/similar ligand(s) or are highly likely to do so. 0490) To identify full-length clones for the the novel Sequence comparisons and phylogenetic analyses (see human GPCR genes that were discovered by the gene below) showed that GPCRs with highly related ligand mining effort, the following methods were used: specificities that are traditionally classed as belonging to the same “family' are at least 40% homologous in protein First-Strand cDNA Synthesis sequence. We therefore assigned GPCRs to specific families 0491 First strand cDNA Synthesis was performed as using the criteria that members of a family either recognize essentially described in the following kit, CLONTECH the same/similar ligand or show at least 40% sequence Laboratories, Inc., Protocol if PT3269-1 16 Version it homology. In this manner, 93 different families of GPCRs PR14596. were identified, including 16 families of orphan receptors 0492. Two 10-ul reactions described below convert 50 that have not been previously described (FIG. 1). These ng-1 lug of total or poly A+RNA into RACE-Ready first studies assigned 12 of 145 human and 47 of 178 mouse strand cDNA. For optimal results, use 1 lug of poly A+RNA orphan GPCRs to seven different families of receptors that or 1 lug of total RNA in the reactions below. interact with known ligands. The orphan receptors in these 0493 1. Combined the following in seperate 0.5-mi families can be predicted to recognize ligands similar to microcentrifuge tubes: those detected by other members of the same family. 0494 For preparation of 5'-RACE-Ready or cDNA 0487. To further investigate sequence-ligand relation 3'-RACE-Ready cDNA ships among human GPCRs, we conducted a phylogenetic 0495) 1-3 ul RNA sample 1-3 ul RNA sample analysis. GPCRs were aligned to the class specific HMM profile model using the HMMALIGN program of the 0496) 1 Jul 5'-CDS primer 1 ul 3'-CDS primer A HMMER package. These alignments were used for the 0497. 1 ul SMART II A oligo construction of phylogenetic trees, using the Clustal W program. The phylogenetic trees were then overlaid with 0498 2. Add sterile HO to a final volume of 5ul for each information on the ligand specificities of individual recep reaction. tors, where available. 0499 3. Mix contents and spin the tubes briefly in a microcentrifuge. 0488 The combined phylogenetic/ligand analyses of human GPCRs are shown in FIG. 2. The phylogenetic tree 0500 4. Incubate the tubes at 70° C. for 2 min. of the class A receptors, the largest set, was composed of a 0501) 5. Cool the tubes on ice for 2 min. number of major branches that were progressively Subdi 0502 6. Spin the tubes briefly to collect the contents at vided into Smaller branches containing increasingly related the bottom. GPCRs. The three smaller classes of receptors (classes B, C, and F/S) exhibited a similar organization, but fewer 0503 7. Add the following to each reaction tube (already branches. GPCRs that recognize the same ligand. Such as containing 5 ul): receptors for the neurotransmitter acetylcholine, or receptors 0504 2 ul 5x First-Strand buffer that belong to the same family, were clustered together in Small branches. 0505] 1 ul DTT (20 mM) 0489. The phylogenetic trees, in addition, revealed a 0506 1 ul dNTP Mix (10 mM) striking, higher order organization relevant to GPCR func 0507 1 ul PowerScript Reverse Transcriptase tions. Multiple receptor families with related functions that 0508) 10 ul Total volume recognize ligands of a particular chemical class were grouped in the same large branch. For example, the 40 0509) 8. Mix the contents of the tubes by gently pipetting. neurotransmitter/neuromodulator receptors of the dopamine, 0510) 9. Spin the tubes briefly to collect the contents at serotonin, trace amine, adenosine, acetylcholine, histamine the bottom. and adrenoreceptor a and B families were all clustered phylogenetically. Moreover, the 106 GPCRs known to rec 0511) 10. Incubate the tubes at 42°C. for 1.5 hr in an air ognize peptide ligands were clustered in four large branches, incubator. three in the class A tree and one in the class B tree. This 0512 11. Dilute the first-strand reaction product with organization is of predictive value for numerous orphan Tricine-EDTA Buffer: GPCRs. For example, GPCRs such as PGR2, PGR3, 0513. Added 20 ul if started with <200 ng of total RNA. PGR11, GPR19, GPR37, GPR39, GPR45, GPR63 and GPR103 could be predicted to have peptide ligands since 0514 * Added 100 ul if started with >200 ng of total they were grouped with other receptors activated by pep RNA. tides. Other orphan receptors, such as GPR21 and GPR52 0515 * Added 250 ul if started with poly A+RNA. could conceivably be activated by amine neuromodulators, as they clustered phylogenetically with amine-type mol 0516) 12. Heat tubes at 72° C. for 7 min. ecules in the large neurotransmitter branch of the class A 0517 13. Samples can be stored at -20°C. for up to three tree. months. US 2006/0134109 A1 Jun. 22, 2006

0518) Now have 3'- and 5'-RACE-Ready cDNA samples. 0540 RNaseCut (40 U/ul) 1 ul 3' and 5 RACE 0541) Total Volume 20 ul 0519) 1. Treat total RNA or mRNA with calf intestinal 0542. The reaction was incubated at 45° C. for 1 hour and phosphatase (CIP) to remove the 5' phosphates. This elimi then at 85°C. for 15 minutes to inactivate the cloned AMV nates truncated mRNA and non-mRNA from subsequent RT. ligation with the GeneRacer RNA Oligo. Dephosphorylation 0543) 5. To obtain 5' ends, amplify the first-strand cDNA reaction was set up in a 1.5 ml sterile microcentrifuge tube using a reverse gene specific primer (Reverse GSP) and the using the reagents in the kit. 1-5 g total RNA was used in GeneRacer 5' Primer. Only mRNA that has the GeneRacer a total volume of 10 ul with 10x RNaseCut and CIP (10 U). RNA Oligo ligated to the 5' end AND is completely reverse The reaction was incubated at 50° C. for 1 hour. After transcribed will be amplified using PCR. If needed, perform incubation, the RNA was precipitated with ethanol. additional PCR with nested primers. 0520 2. Treat dephosphorylated RNA with tobacco acid 0544 6. To obtain 3' ends, amplify the first-strand cDNA pyrophosphatase (TAP) to remove the 5' cap structure from using a forward gene-specific primer (Forward GSP) and the intact, full-length mRNA. This treatment leaves a 5' phos GeneRacer 3' Primer. Only mRNA that has a polyA tail and phate required for ligation to the GeneRacer RNA Oligo. is reverse-transcribed will be amplified using PCR. If 0521. The reaction was set up on ice the using the needed, perform additional PCR with nested primers. reagents in the kit. PCR Conditions Used for 3' or 5' RACE or Internal Frag 0522 Dephosphorylated RNA 7 ul ment Amplification 0545 PCR was performed using the following cycle 0523) 10x TAP Buffer 1 ul parameters, 94 C for 2 minutes for melting, then (94 C for 0524 RNaseCut (40 U/ul) 1 ul 30 sec; 67 C for 1 minute; 72 C for 1.5 minutes) for 6 cycles, then (94 C for 30 seconds, 60 C for 1 minute, 72 C for 1.5 0525) TAP (0.5 U?ul) 1 ul minutes) for 38 cycles, then 72 C for 7 minutes and then hold 0526 Total Volume 10 ul at 4 C. 0527 The reaction was incubated at 37° C. for 1 hour. 0546 7. Purify RACE PCR products using the S.N.A.P. After incubation, the RNA was precipitated with ethanol. columns included in the kit. 0528) 3. Ligate the GeneRacer RNA Oligo to the 5' end Rapid Amplification of cDNA Ends (RACE) of the mRNA using T4 RNA ligase. The GeneRacer RNA 0547. This procedure describes the 5'-RACE and Oligo will provide a known priming site for GeneRacer. 7 ul 3'-RACE PCR reactions that generate the 5' and 3' cDNA of dephosphorylated, decapped RNA was incubated at 65° fragments. C. for 5 minutes. Then the following were added: 0548 1. For each 50-ul reaction, mix the following 0529) 10x Ligase Buffer 1 ul reagents: 0530 10 mM ATP 1 ul 0549) 34.5 ul PCR-Grade Water 0531) RNaseCut. (40 U/ul) 1 ul 0550) 5 ul 10x Advantage 2 PCR Buffer 0532 T4 RNA ligase (5 U?ul) 1 ul 0551) 1 ul dNTP Mix (10 mM) 0533) Total Volume 10 ul 0552) 1 ul 50x Advantage 2 Polymerase Mix 0534. After incubation, 90 ul of DEPC treated water was 0553) 41.5 ul Total volume added and the reaction was extracted with phenol/chloro form, and precipitated with the addition of 2 ul of 10 mg/ml 0554 Mix well by vortexing (without introducing mussel glycogen, 10 Jul 3M sodium acetate, pH 5.2 and 220 bubbles) and briefly spin the tube in a microcentrifuge. ul of 95% ethanol. 0555 2. For 5'-RACE: PCR reactions as shown in Table 0535 4. Reverse-transcribe the ligated mRNA using III of Clontech's RACE kit. Cloned AMV RT or SuperScript II RT and the GeneRacer. 0556). For 3'-RACE: PCR reactions as shown in Table IV OligodT Primer to create RACE-ready first-strand cDNA of Clontech's RACE kit. with known priming sites at the 5' and 3' ends. 0557. PCR Cycle conditions: as described in the Clon 0536 To 10 ul ligated mRNA, 1 ul of the desired primer tech's RACE kit. was added and 1 ul of dNTPMix (25 mM each) to the ligated RNA. Then the mixture was incubated at 65° C. for 5 0558 Complete reactions were then run on gel to visu minutes to remove any RNA secondary structure, chilled on alize PCR products. If the gel showed nothing then the ice for 2 minutes and added the following reagents to the reaction would be amplified for additional cycles (total of ligated RNA and primer mixture: 40). 0537) 5xRT Buffer 4 ul Human PGR4 0559) Full length cDNA was isolated from human Pitu 0538 Cloned AMV RT (15 U?ul) 1 ul itary by a combination of 5' and 3' Rapid Amplification of 0539 Sterile water 2 ul cDNA Ends (RACE) and internal RT-PCR experiments

US 2006/0134109 A1 Jun. 22, 2006 53

- continued GGAAATTTCGATTTGCACACTGATTTGGCCCACCATTCCTGGAGAGATCTCGTG

GGATGTCTCTTTTGTTACTTTGAACTTCTTGGGCCAGGACTGGTCATTGTGATC

AGTTACTCCAAAATTTTACAGATCACAAAGGCATCAAGGAAGAGGCTCACGGT

AAGCCTGGCCTACTCGGAGAGCCACCAGATCCGCGTGTCCCAGCAGGACTTCCG

GCTCTTCCGCACCCTCTTCCTCCTCATGGTCTCCTTCTTCATCATGTGGAGCCCC

ATCATCATCACCATCCTCCTCATCCTGATCCAGAACTTCAAGCAAGACCTGGTC

ATCGGCCGTCCCTCTCTCTGGGGGTGGCCTTCACATTGCTAATTCAGCCC

TAAACCCCATCCTCTACAACATGACACTGTGCAGGAATGAGTGGAAGAAAATTT

TTTGCTGCTTCTGGTTCCCAGAAAAGGGAGCCATTTTAACAGACACATCTGTCA

AAAGAAATGACTTGTCGATTATTTCTGGCTAATTTTTCTTATAGCCGAGTTCT

CACACCTGGCGAGCTGTGGCATGCTTTTAAACAGAGTTCATTTCCAGTACCCTC.

CATCAGTGCACCCTGCTTTAAGAAAATGAACCTATGCAAATAGACATCCACAGC

GTCGGTAAATTAAGGGGTGATCACCAAGTTTCATAATATTTTCCCTTTATAAAA

GGATTTGTTGGCCAGGTGCAGTGGTTCATGCCTGTAATCCCAGCAGTTTGGGAG

GCTGAGGTGGGTGGATCACCTGAGGTCAGGAGTTCGAGACCAACCTGACCAAC

ATGGTGAGACCCCCGTCTCTACTAAAAATAAAAAAAAAAATTAGCTGGGAGTG

GTGGTGGGCACCTGTAATCCTAGCTACTTGGGAGGCTGAACCAGGAGAATCTCT

TGAACCTGGGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCACTCCA

ACCAGGGCAACAAGAGTGAAACTCCATCTT

0563)

PGR4 polypeptide sequence (SEQ ID NO : 87) MSPECARAAGDAPLRSLEQANRTRFPFFSDWKGDHRLVLAAVETTWLVLIFAVSLL

GNWCALWLWARRRRRGATACLWLNLFCADLLFISAIPLWLAWRWTEAWLLGPWAC

HLLFYVMTLSGSWTILTLAAVSLERMVCIVHLQRGWRGPGRRAPAVILLALIWGYSA

WAALPLCWFFRVWPQRLPGADQEISICTLIWPTIPGEISWDWSFWTLNFLWPGLVIVIS

YSKILOITKASRKRLTVSLAYSESHOIRVSQQDFRLFRTLFLLMVSFFIMWSPIIITILLI

LIONFKQDLVIWPSLFFWWWAFTFANSALNPILYNMTLCRNEWKKIFCCFWFPEKG

AILTDTSWKRNDLSIISG

Human PGR2 0564) Full length cDNA was isolated from human uterus -Continued by a combination of 5' and 3' Rapid Amplification of cDNA 5' nested RACE primer: Ends (RACE) and internal RT-PCR experiments as GGACACTGACATGGACTGAAGGAGTA (SEQ ID NO: 1547) described above. RACE pituitary was prepared using the ima - a Invitrogen GeneRacer Kit (Cat # L1 500-01). 3' nested RACE primer: CGCTACGTAACGGCATGACAGTG (SEQ ID NO: 1548) 0565. The following RACE primers were used: 0566) The following cDNA primers were used: 5' RACE (Invitrogen) 3RaceUp CGACTGGAGCACGAGGACACTGA (SEQ ID NO: 1545) ACTACCTTCTGGCGCTCACA (SEQ ID NO: 1561) 3' RACE (Invitrogen) : 5RaceDn GCTGTCAACGATACGCTACGTAACG (SEQ ID NO: 1546) CCCAGCAGGACACTGTAGTAGA (SEQ ID NO: 1562)

US 2006/0134109 A1 Jun. 22, 2006

Human PG3 -continued 0569. Full length cDNA was isolated from human whole Hipg10-02up brain by a combination of 5' and 3' Rapid Amplification of CGGCCAAGGGTAGGAGCCAGTCCTG (SEQ ID NO: 1573) cDNA Ends (RACE) and internal RT-PCR experiments as described above. RACE pituitary was prepared using the Hpg 10-02dn CTTGAGCGGGTGGCAGACAGCGATA; (SEQ ID NO: 1574) Invitrogen GeneRacer Kit (Cat # L1500-01). used in 5 RACE 0570) The following RACE primers were used: Hipg10-03up GGGTTTCGTGCCCGTGGTCTACT (SEQ ID NO: 1575)

5' RACE (Invitrogen) Richigarcaccorgot SEO ID NO 1576 CGACTGGAGCACGAGGACACTGA (SEQ ID NO: 1545) (SEQ ) 3' RACE (Invitrogen) : Eigtaccaca SEO ID NO 1577 GCTGTCAACGATACGCTACGTAACG (SEQ ID NO: 1546) (SEQ ) 5' nested RACE primer: Earcacacaccre SEO ID NO 1578 GGACACTGACATGGACTGAAGGAGTA (SEQ ID NO: 1547) (SEQ ) 3' nested RACE primer: Erificaccartaccre SEO ID NO 1579 CGCTACGTAACGGCATGACAGTG (SEQ ID NO: 1548) f (SEg ID no: ) used in 3 RACE Hpg 10-05dn 0571. The following cDNA primers were used: CATTACGACTTTTTATAGGTTTTCC (SEQ ID No: 1580) Hipg10g O1 up Hipg10max5up CACCGAGCCGGCGACCAGAGTC (SEQ ID NO: 1581) ATGGAGCACACGCACGCCCACCTCG (SEQ ID NO: 1571) Hipg10g Oldn Hpg 10max5.dn TGAGCGGGTGGCAGACAGCGAT (SEQ ID NO: 1582) TCATGATGATGCGGGGGGCCCAAAG (SEQ ID NO: 1572) 0572)

PGR3 cDNA sequence (SEQ ID NO : 54) CTGCATCTTCTCCCCTGAAAGTGGAGCCAAGCGAGGCGGCTGGGACCCCCTCCT

CTTCCGCATCCCTCCCACCCCACACACACTCCGCTTCCAGGCAGCCGCTGATTG

GCTGCGGGGAGCGGCGTCCCAGCCCCCCGGCTTTGAGGCGGGAGTGGAGCGGG

TCCGAGGTGGGAGGCGCACAGACGGGCTCCGGGAGCCCCTCCCGAGGCCCCGC

GCAGCGCGCCCCGCACCCTGCGCCCCGCGCCCTGCGGGAGGGCTGAGCCAAGA

CTCCAGGCGGGCAGGTGCGGAGCGAGCAGAGGGGATCACGGCCAAGGGTAGG

AGCCAGTCCTGCGGGGAGAGAGGCGCTGCTGCTCCAGCTGCCGCTGCCTCCGCC

GCCGCCACCACCGAGCCGGCGACCAGAGTCGGGCTGGCAGGCCGGGCGCGAAG

CGGCAAGGGGAGCGAGGGGCGCGCTCATGGAGCACACGCACGCCCACCTCGCA

GCCAACAGCTCGCTGTCTTGGTGGTCCCCCGGCTCGGCCTGCGGCTTGGGTTTC

GTGCCCGGGTCTACTACAGCCTCTTGCTGTGCCTCGGTTTACCAGCAAATACT

TGACAGTGATCATCCTCTCCCAGCTGGTGGCAAGAAGACAGAAGTCCTCCTACA

ACTATCCTTGGCACTCGCTGCTGCCGACATCTTGGTCCCTTTTTCATAGGTTT

GTGGACTTCCTGTTGGAAGATTTCATCTTGAACATGCAGATGCCTCAGGTCCCC

GACAAGATCATAGAAGTGCTGGAATTCTCATCCATCCACACCTCCATATGGATT

ACTGTACCGTTAACCATTGACAGGTATATCACTGTCTGCCACCCGCTCAAGTAC

CACACGGTCTCATACCCAGCCCGCACCCGGAAAGTCATTGTAAGTGTTTACATC

ACCTGCTTCCTGACCAGCATCCCCTATTACTGGTGGCCCAACATCTGGACTGAA

GACTACATCAGCACCTCTGTGCATCACGTCCTCATCTGGATCCACTGCTTCACCG US 2006/0134109 A1 Jun. 22, 2006 57

- continued TCTACCTGGGCCCTGCTCCATCTTCTTCACTTGAACTCAATCATTGTGTACAA

GCTCAGGAGGAAGAGCAATTTTCGTCTCCGTGGCTACTCCACGGGGAAGACCA.

CCGCCATCTTGTTCACCATTACCTCCATCTTGCCACACTTTGGGCCCCCCGCA

CATCATGATTCTTTACCACCTCTATGGGGCGCCCATCCAGAACCGCTGGCTGGT

ACACATCATGTCCGACATTGCCAACATGCTAGCCCTTCTGAACACAGCCATCAA

CTTCTTCCTCTACTGCTTCATCAGCAAGCGGTTCCGCACCATGGCAGCCGCCAC

GCTCAAGGCTTTCTTCAAGTGCCAGAAGCAACCTGTACAGTTCTACACCAATCA

TAACTTTTCCATAACAAGTAGCCCCTGGATCTCGCCGGCAAACTCACACTGCAT

CAAGATGCTGGTGTACCAGTATGACAAAAATGGAAAACCTATAAAAGTATCCC

CGTGATTCCATAGGTGTGGCAACTACTGCCTCTGTCTAATCCATTTCCAGATGG

GAAGGTGTCCCATCCTATGGCTGAGCAGCTCTCCTTAAGAGTGCTAATCCGATT

TCCTGTCTCCCGCAGACTGGGCAATTCTCAGACTGGTAGATGAGAAGAGATGGA

AGAGAAGAAAGGAGAGCATGAAGCTTGTTTTTACTTATGCATTTATTTCCACAG

AGTCGTAATGACAGCAAAAGCTCCTACCAGTTTGAAGATGCCATTGGAGCTTGT

GTCATCATCCTGTGACCAGTTAGGACACAAAGTAGAGAAGTAGTCTGTGATTTC

GCCCTGGTACCATCCACAGTCACTGGGAACCCTTCATTTATGGGACTTACCAAG

CCCCAGTAGCACATAGCTGAGCCTGCACTCTTCTTCCGAGAGCTGAGGTCATTC

ATCACTTCCCTCTGCTGTTCCCAGGAGCTAACAATAATGACTATTTCAGGATTTT

TTTCAAGGTGCCCTTTGTCCTAGAGAGGGTTGTGGTCTTGAATTGGCTCTGGCAC

TCCTAGCTTCAGAATGACACTGTGGGAATAGAAGAGTATTGGATCCCATCCAAA.

CTGTGGCCAGAGCTTCTTCAGGAAATCTCCAAACCCGCATAGCTGTGACCTCAA

ACCTGGGGTCTAAAAGGCAGTTTCTATTATCATTATGTATAGATTTTCCTA

CTCCTCCAAAACAAAGACCCTGCCTGGTGCGCAGGGGGAAAGGAGGAATTCTC

GAGCCC

0573)

PGR3 polypeptide sequence (SEQ ID NO: 53) MEHTHAHLAANSSLSWWSPGSACGLGFWPWWYYSLLLCLGLPANILTWIILSQLWA

RROKSSYNYLLALAAADILWLFFIVFWDFLLEDFILNMQMPQVPDMIIEWLEFSSIHTS

WITWPLTDRYTWCHPLKYHTWSYPARTRKWWSWYTCFLTSIPYYWWPNWTED

YSTSWHHWLWHCFTWYLWPCSFFLNSIWYKLRRKSNFRLRGYSTGKTALFTT

SIFATLWAPRIIMILYHLYGAPIQNRWLWHIMSDIANMLALLNTAINFFLYCFISKRFR

TMAAATLKAFFKCOKQPWQFYTNHNFSITSSPWISPANSHCIKMLWYQYDKNGKPI

KWSP

Human PGR6 0575. The following RACE primers were used: 0574 Full length cDNA was isolated from human whole 5' RACE (Invitrogen) brain by a combination of 5' and 3' Rapid Amplification of CGACTGGAGCACGAGGACACTGA (SEQ ID NO: 1545) cDNA Ends (RACE) and internal RT-PCR experiments as 3' RACE (Invitrogen): described above. RACE pituitary was prepared using the GCTGTCAACGATACGCTACGTAACG (SEQ ID NO: 1546) Invitrogen GeneRacer Kit (Cat # L1500-01).

US 2006/0134109 A1 Jun. 22, 2006 61

- continued ATCCAAAAGTGTTGGCCATGAACCAAACTCAGAAGATTCTTCATCCACGTTTGT

GGACACCAGTGTGAAAATACACTTGGAGGTTCTTGAAATTTGTGATAATGAAGA

GGCCTTGGACACTGTGTCAATCATTAGTAACATCAGTCAGTCCTCCACACAAGT

CAGATCTCCATCCCTACGTTACTCCAGGAAAGAAAACAGATTTGTTTCATGTGA

CCTAGGGGAAACAGCCTCATACTCCCTCTTTTTGCCCACCAGTAATCCTGATGG

TGATATTAATATCTCCATTCCAGACACAGTAGAAGCACACAGGCAGAACAGTA

AAAGGCAGCATCAAGAGAGGGATGGCTACCAGGAGGAAATCCAGTTGTTAAAT AAAGCTTACAGAAAAAGAGAGGAAGAAAGCAAGGGTAGTTAGTGGGTATTTG

GTCTAACAGGAGCAAGAATGGATCTGCAACGTCAACTGTGAAACTAACACCTTT

GTTAGAGACTGATTTCCTTTTATTGTTGGCTTACATTAGTTTTACTGATTTAAT

AGTTAATTTTTTTGTGGGAACAACTGGAACTAGTGTAAACACTTAAGTGCATTT

GATGTGTTACCTAAAGATCACACACTGTGGTAATGAAAAGATTTTACTTCTTAT

CTGACTTCTAAAAAATATTTTCTAAATCAAATCTTGGCCTAGTTTACCAATGTTT

TTGCTTGTCAACTTCCTAGTAAACAGAAAATTGTATAAACTCAGTGAATATACT

GTTCCATGCATATGTTTCTATATACAATGTTGGCCTTTACTGCAAAGGGGAAAA

AAGAGGAATTCTGGGAATGGAAGAAATGTAACAAAACCCCAAATTATATTT

0583)

PGR10 polypeptide sequence (SEQ ID NO: 5) MSLFLSNLSTNDSSLWKENHNSTDLLNPPGTLNIYLFCLTCLMTFAALWGSIYSLISL

LKMONRTVVSMLVASWSVDDLMSWLSVTIFMFLOWPNEWPGYFOFLCTTSALMY

LCOGLSSNLKATLLWSYNFYTMHRGWGSQTASRRSGQWLGVWLTVWAASLLLSAL

PLCGWGAFWRTPWGCLWDCSSSYWLFLSIWYALAFGLLWGLSWPLTHRLLCSEEPPR

LHSNYQEISRGASIPGTPPTAGRVWSLSPEDAPGPSLRRSGGCSPSSDTVFGPGAPAA

AGAEACRRENRGTLYGTRSFTWSWAQKRFALILALTKWWLWLPMMMHMVVONVW

GFQSLPLETFSFLLTLLATTWTPWFWLSKRWTHLPCGCIINCRONAYAVASDGKKIK

RKGFEFNLSFQKSYGIYKIAHEDYYDDDENSIFYHNLMNSECETTKDPQRDNRNIFN

AIKVEISTTPSLDSSTORGINKCTNTDITEAKQDSNNKKDAFSDKTGGDINYEETTFS

EGPERRLSHEESQKPDLSDWEWCRSKSERTPRQRSGYALAIPLCAFOGTVSLHAPT

GKTLSLSTYEWSAEGOKITPASKKIEWYRSKSVGHEPNSEDSSSTFWDTSVMIHLEVL

EICDNEEALDTVSIISNISQSSTOVRSPSLRYSRKENRFWSCDLGETASYSLFLPTSNP

DGDINISIPDTWEAHRQNSKRQHQERDGYQEEIQLLNKAYRKREEESKGS

Human PGR25 0585. The following CLONTECH RACE primers were used: 0584 Full length cDNA was isolated from human Pitu itary by a combination of 5' and 3 Rapid Amplification of (SEQ ID NO: 1597) cDNA Ends (RACE) and internal RT-PCR experiments as accorcorrcaacgcAGAgracterpretirrrrrrrrt described above. RACE pituitary was prepared using the TTTTTTTTTTWN Clontech SMART RACE Kit (Cat # K 811-1).

US 2006/0134109 A1 Jun. 22, 2006 65

0592)

PGR17 cDNA sequence (SEQ ID NO: 30) TTCTTCTTTCATTTCACATCAAACATAGGAATTTAGAGACAAGATCTGGTCATTT GAGGGTGGGAAGTTAAAAGAGTCCAGTTCTCAGACTTAGACAATGAAAGAACA

CATCATATATCAGAAGCTTAGGATTGATTCTCATGTCGAGTTTTACTTTCC

TCAGATACACTTTCACTAAAAGGAAAAAAGCTGGATTTTTTTGGAAGAGGTGAC

ACATATGTAAGCCTGATAGATACCATTCCTGAACTCAGCCGATTCACAGCATGC

ATTGATCTGGTATTCATGGATGACAACTCAAGGTATTGGATGGCCTTCTCTTATA

TTACTAATAACGCCCTCCTGGGCAGAGAAGACATAGACCTTGGACTTGCAGGA

GACCATCAGCAGCTAATACTATACAGATTGGGAAAGACCTTTTCTATCCGTCAC

CACCTGGCTTCATTTCAATGGCATACAATATGCTTGATATGGGATGGTGTGAAG

GGCAAATTAGAACTCTTCCTGAATAAAGAAAGGATACTGGAAGTAACGGATCA.

ACCACACAACCTGACACCTCATGGGACTCTGTTCCTAGGGCACTTTCTCAAGAA

TGAGAGCAGCGAGGTTAAAAGCATGATGCGTAGCTTTCCTGGCAGCTTGTACTA

CTTTCAACTCTGGGACCACATCCTGGAAAACGAAGAGTTTATGAAGTGTTTAGA

TGGAAATATAGTTAGTTGGGAAGAAGACGTCTGGCTTGTCAACAAGATCATCCC

AACTGTTGACAGGACACTGCGCTGCGTTCCTGAAAATATGACAATTCAAGAAA

AAAGTACAACTGTTTCACAACAGATAGATATGACCACTCCATCCCAAATTACTG

GAGTAAAACCACAAAATACTGCACATTCCTCTACACTATTGTCTCAAAGCATAC

CTATATTTGCAACTGATTACACAACCATATCATATTCCAATACAACATCTCCACC

TCTGGAAACAATGACTGCACAAAAAATCTTAAAGACACTGGTAGATGAGACAG

CTACATTTGCAGTGGATGTTTTATCAACTTCACAGCCATCTCTCTGCCTACCCA

GAGTATATCCATAGACAATACTACCAATTCCATGAAAAAAACGAAATCTCCATC

TTCAGAAAGCACAAAGACAACAAAAATGGTTGAAGCCATGGCTACTGAAATCT

TTCAACCACCTACACCTTCTAATTTCCTATCCACATCCAGATTTACCAAGAATTC

AGTTGTATCTACAACTTCAGCAATTAAATCTCAGTCGGCTGTTACGAAGACAAC

ACTTATTTTCAACTATTGAGTCAACATCTATGTCTACAACACCTTGTCCAAA

CAAAAATCCACAAATACTGGGGCACTCCCTATCTCCACAGCTGGCCAGGAGTTC

ATTGAATCTACAGCTGCCGGAACTGTACCTTGGTTTACAGTGGAAAAGACTTCA

CCTGCATCTACTCATGTTGGGACTGCATCATCATTCCCACCTGAGCCTGGCTCA

TCTCCACAGCTGCTCCAGTAGATTCTGTATTTCCTAGAAACCAGACAGCATTTCC

ATTGGCAACAACTGATATGAAAATAGCATTTACAGTCCATTCATTGACTCTCCC

AACTAGGCTTATTGAGACCACACCTGCCCCAAGGACAGCTGAAACAGAATTGA

CATCTACAAATTTTCAGGATGTCTCTTTACCCAGAGTGGAAGATGCCATGTCTA

CTTCCATGTCGAAAGAGACCTCCTCTAAG ACCTTTTCTTTCTTAACATCCTTTTC

ATTTACTGGGACTGAGAGTGTACAGACAGTTATTGATGCTGAAGCTACACGTAC

AGCCTTAACTCCTGAAATCACACTTGCATCTACAGTGGCTGAAACTATGCTTTC

CTCCACAATCACAGGACGAGTTTACACCCAGAATACACCTACAGCTGATGGAC

ACTTGCTTACTTTGATGTCCACTAGATCAGCTTCCACATCCAAGGCACCTGAGTC US 2006/0134109 A1 Jun. 22, 2006 66

- continued AGGTCCCACATCCACAACTGATGAAGCTGCCCATCTGTTCTCCAGCAATGAGAC

CATTTGGACTTCTAGGCCAGACCAGGCCCTGCTGGCATCTATGAACACAACCAC

CATACT CACATTTGTGCCTAATGAAAATTTTACATCAGCATTTCATGAGAATACT

ACTTATACAGAATATTTATCCGCAACTACCAATATCACCCCACTGAAAGCATCT

CCAGAGGGCAAAGGTACCACTGCCAATGATGCTACTACAGCCAGATATACAAC

AGCTGTATCCAAATTGACATCACCATGGTTTGCTAATTTCTCCATAGTTTCTGGA

ACCACATCCATAACCAATATGCCTGAATTTAAACTTACCACTTTACTACTAAAA

ACAATACCTATGTCTACAAAACCTGCAAATGAACTTCCTTTGACACCAAGGGAG

ACTGGTTCCATCAGTAGATATAAACTACTCTTGCTTGCATTCAACCAAATT

TTTCTACTGAGGAAAGTGCTTCTGAGACCACACAAACAGAAATAAATGGTGCA

ATTGTATTTGGAGGTACAACGACCCCTGTACCAAAGTCAGCAACAACACAAAG

ATTAAATGCCACTGTGACAAGAAAAGAAGCAACTTCCCATTATCTTATGAGAAA

ATCAACTATAGCAGCAGTGGCTGAGGTTTCTCCATTTTCAACAATGCTGGAAGT

GACAGACGAATCAGCACAAAGGGTGACAGCTTCTGTCACTGTTTCCTCTTTTCC

TGATATAGAAAAGCTAAGTACCCCATTGGATAATAAAACTGCAACAACTGAGG

TGAGAGAAAGTTGGCTTTTGACAAAATTGGTGAAAACCACACCTAGGAGTTCAT

ACAATGAAATGACAGAAATGTTTAATTTTAACCACACCTATGTAGCACATTGGA

CTTCAGAGACATCTGAGGGAATTTCAGCTGGATCTCCCACTTCTGGGAGCACAC

ATATATTCGGTGAACCCCTGGGTGCTTCTACCAGAAGGATATCAGAAACCAGTT

TCTCCACTACCCCTACAGACAGGACAGCTACGTCCTTGTCTGATGGTATCTTACC

TCCACAGCCTACAGCTGCTCATTCCTCAGCAACCCCTGTGCCTGTTACTCATATG

TTCTCATTGCCAGTTAATGGCAGTTCTGTGGTGGCTGAGGAGACTGAGGTTACC

ATGTCTGAGCCTTCACACTGGCCAGGGCTTTTTCTACATCTGTGCTCTCAGATG

TCTCAAATCTATCCTCAACTACAATGACCACAGCATTGGTACCACCTTTGGATC

AGACTGCTTCCACAACCATTGTTATTGTGCCTACCCATGGAGACTTGATTCGTAC

CACTTCAGAGGCCACGGTAATCTCTGTCAGGAAGACATCCATGGCAGTTCCTTC

TCTGACAGAAACACCATTTCATTCACTGAGACTCTCCACTCCTGTGACAGCTAA

GGCTGAGACCACCCTTTTCTCTACCTCAGTTGATACAGTAACCCCATCTACACA

CACTCTTGTCTGCCAAAACCTCCCCCTGACAACATTCCTCCTGCGTCCTCCACT

CATGTGATCTCAACTACGTCTACACCAGAAGCAACTCAACCAATATCTCAAGTA

GAGGAGACTTCTACCTATGCTCTCAGCTTCCCATATACTTTCAGTGGTGGTGGA

GTTGTTGCCAGCTTGGCTACTGGCACCACAGAGACCTCTGTTGTTGATGAGACC

ACACCCTCACACATCTCTGCCAATAAGTTGACTACTTCAGTAAACAGTCACATT

TCTTCATCTGCCACATATCGTGTACACACACCAGTGTCCATCCAGTTGGTGACTA

GCACCTCTGTCTTATCTTCCGACAAAGACCAGATGACCATATCCCTGGGAAAAA

CCCCTAGAACTATGGAGGTGACAGAAATGTCCCCATCAAAGAATTCTTTTATTT

CATACTCCCGGGGTACTCCATCTTTGGAAATGACAGATACAGGATTTCCTGAGA

CCACAAAAATTTCCAGTCACCAAACACATTCGCCTTCAGAGATTCCACTTGGGA

CTCCCTCTGATGGAAATTTGGCTTCATCTCCCACTTCTGGAAGCACACAGATTAC US 2006/0134109 A1 Jun. 22, 2006 67

- continued

ACCAACCTTGACCTCAAGTAACACAGTAGGTGTTCACATTCCAGAAATGTCTAC

CAGTCTTGGGAAAACAGCTCTCCCCTCACAAGCTCTGACAATCACCACTTTTTT

GTGTCCTGAAAAGGAAAGCACGAGTGCCCTTCCAGCATATACTCCCAGGACTGT

GGAAATGATAGTAAACTCCACCTATGTGACT CACTCTGTCTCATATGGCCAGGA

TACTTCATTTGTAGATACCACAACTTCCAGCTCAACAAGGATATCAAATCCTAT

GGACATCAATACAACTTTTTCACACTTGCATTCACTTAGGACACAACCTGAGGT

GACTTCAGTTGCCTCTTTCATTTCTGAAAGCACACAGACTTTCCCTGAGCCTTG

TCTCTTTCCACAGCTGGACTATATAATGACGGTTTTACAGTTCTCTCCGACAGGA

TCACTACAGCCTTTTCTGTTCCAAATGTACCTACAATGCTTCCTAGAGAATCCTC.

TATGGCAACGTCCACTCCTATTTACCAGATGTCCTCATTGCCAGTTAATGTAACT

GCCTTCACCTCCAAAAAAGTTTCTGACACTCCCCCAATAGTGATAACTAAATCT

TCTAAAACAATGCATCCAGGTTGTTTGAAAAGTCCCTGTACAGCCACTTCTGGG

CCTATGTCTGAGATGTCCTCAATACCAGTTAATAACTCTGCTTTCACACCTGCAA

CAGTCTCTTCTGACACTCCACAAGAGTTGGGTTATTCTCTACTTATTGTCTTC

AGTTACCCCCAGGACTACTATGACCATGCAAACATCTACATTGGATGTCACACC

TGTGATATATGCTGGGGCTACTTCAAAAAACAAAATGGTTTCCTCTGCTTTCACT

ACAGAAATGATAGAGGCACCTTCCAGGATCACACCTACGACCTTTCTCTCTCCA

ACAGAGCCAACTTTGCCCTTTGTAAAAACCGTTCCCACCACCATTATGGCTGGG

ATAGTGACTCCATTTGTAGGCACCACTGCCTTCTCTCCACTCAGTTCTAAGAGCA

CTGGAGCTATTTCCTGCATTCCAAAGACCACATTTTCACCATTTCTATCAGCAAC

TCA ACAGTCATCAGAAGCAGATGAGGCTACAACTTTGGGCATATTATCTGGGAT

TACTAACAGGTCCCTATCTACTGTGAACAGTGGTACAGGGGTAGCTCTCACAGA

TACTTATTCCAGAATCACTGTTCCTGAAAATATGCTTTCACCTACTCATGCAGAT

AGTCTCCAACTTCCTTCAAATTCAGGTTTCCCCATCTCTGACTAGCTTTAAGA

GTGCTTCTGGACCCACAAAAAATGTTAAAACAACCACCAATTGCTTTTCTTCTA

ATACTAGAAAGATGACTTCCTTGTTAGAAAAGACTTCCTTAACAAACTATGCCA

CATCTTTGAATACCCCTGTTTCATACCCTCCATGGACCCCACCAGTGCAACTCT

ACCCTCTTGACATCATTTGTTTATTCACCTCATAGTACTGAAGCTGAGATCTCT

ACTCCAAAGACCTCTCCTCCTCCCACATCCCAAATGGTTGAATTTCCAGTTCTGG

GAACAAGAATGACATCTAGTAATACCCAACCTCTGCTTATGACTTCCTGGAACA

TACCCACAGCTGAAGGTTCTCAGTTTCCAATTTCCACCACTATTAATGTACCTAC

ATCCAATGAGATGGAAACAGAGACTCTACACCTTGTTCCTGGGCCTTTGTCAAC

ATTCACAGCCTCTCAGACTGGTCTAGTATCTAAAGATGTCATGGCAATGTCATC

AATTCCTATGTCAGGAATTCTTCCTAACCATGGGCTTTCTGAGAACCCTTCATTA

TCAACATCTTTAAGAGCTATCACTTCCACATTGGCTGACGTTAAGCACACATTT

GAGAAAATGACCACATCTGTAACTCCTGGGACCACACTCCCATCAATTCTTTCT

GGTGCCACTTCAGGATCTGTAATTTCAAAGTCACCCATTCTGACATGGCTCTTAT

CTAGTCTCCCTTCTGGCTCCCCTCCGGCAACTGTATCTAATGCCCCTCATGTTAT US 2006/0134109 A1 Jun. 22, 2006 68

- continued GACTTCCTCTACAGTAGAGGTGTCAAAATCAACATTTCTGACATCTGACATGAT

ATCAGCGCACCCATTCACTAACTTGACAACACTACCCTCTGCTACTATGAGCAC

CATACT CACCCGAACCATTCCTACACCTACACTGGGTGGTATCACTACTGGCTT

CCCAACTTCTCTCCCTATGTCTATAAATGTCACAGATGACATTGTGTACATTTCC

ACACACCCTGAGGCATCCTCCAGAACCACAATAACTGCCAACCCCAGGACTGT

GTCTCATCCTTCATCCTTCAGCAGAAAGACTATGTCACCTTCTACAACTGACCAC

ACTCTACTGTTGGGCCAGCCTCGCCTAGCTCTACAATAACATCTTCAGGA

ACAGAATTCCAACTGCATCATCACCCTCTACTTTAATTATTCCTAAGCCCACACT

GGACTCCCTTCTAAATATAATGACTACTACATCCACTGTTCCTGGAGCCTCATTT

CCACTCATATCCACTGGGGTGACATATCCTTTTACAGCAACTGTGTCTTCACCAA

TATCGTCCTTTTTTGAAACAACTTGGCTGGACTCCACACCTTCCTTTCTATCTAC

GGAAGCATCGACTTCGCCTACTGCCACCAAGTCCACAGTTTCCTTCTACAATGT

TGAAATGAGCTTCTCTGTCTTTGTTGAAGAGCCAAGGATCCCTATTACCAGTGTT

ATAAATGAATTTACGGAAAATTCGTTGAATTCTATATTTCAGAACAGTGAATTT

TCTCTTGCTACTCTGGAAACCCAAATTAAAAGCAGGGACATTTCAGAGGAAGA

GATGGTCATGGATCGAGCTATTTTGGAACAGAGAGAAGGACAAGAAATGGCTA

CAATTTCCTATGTACCATACAGTTGTGTTTGTCAGGTCATCATAAAAGCCAGCTC

TTCCTTAGCATCCTCTGAATTGATGAGAAAAATCAAAAGTAAAATACATGGCAA

CTTCACACATGGAAACTTCACACAAGATCAATTGACGTTATTAGTAAACTGTGA

ACACGTTGCAGTGAAAAAACTAGAGCCTGGAAATTGCAAAGGTGATGAAACAG

CCTCTAAATACAAAGGGACCTATAAGTGGCTATTAACCAACCCTACGGAGACA

GCCCAAACCAGATGCATAAAAAATGAGGATGGAAATGCCACAAGATTCTCAAT

CAGCATCAACACGGGCAAATCTCAGTGGGAAAAGCCAAAGTTTAAACAATGCA

AATTGCTTCAAGAACTTCCTGACAAGATTGTGGATCTTGCTAATATTACCATAA

GTGATGATTTTCCTAGGCAATGTCCCTGTGGGAGGGATTTTGGCTCCAAATT TGCCTAAATCACTGACGGAGAGAATTCCTCTTAGCAACTTACAAACGATCTTGT

TTAATTTCTTTGGCCAAACTTCACTCTTTAAGACCAAAAATGTCACTAAAGCATT

AACCACCTATGTTGTGAGTGCCAGCATTTCAGATGATATGTTCATTCAAAACTT

AGCTGACCCAGTGGTTATCACTCTGCAGCATATTGGAGGAAACCAGAATTATGG

TCAAGTTCACTGTGCCTTTTGGGATTTTGAGAATAATGGGCTGGGTGGATGGAA

TTCGTCAGGCTGTAAAGTAAAGGAAACAAATGTAAATTACACAATCTGTCAGTG

TGACCACCTCACCCATTTTGGAGTCTTAATGGAAACTTCGAAAAGATTATCCTG

CCAAAATTCTGATCAACCTGTGCACAGCACTACTGATGCTAAACCTGGTATTTT

TGATCAATTCTTGGTTGTCATCATTTCAGAAAGTGGGAGTTTGTATCACAGCTGC

AGTGGCACTCATTACTTCCTGCTTGTTTCTTTTACTTGGATGGGCCTGGAGGCA

GTCCACATGTATTTGGCTCTAGTCAAAGTCTTCAACATATACATTCCAAATTATA

TCCTTAAATTTTGTCTAGTTGGTTGGGGAATCCCGGCTATCATGGTGGCAATCAC

AGTCA,

US 2006/0134109 A1 Jun. 22, 2006

TABLE 1-continued TABLE 2-continued

GPCRs Novel GPCRs

Human Mouse Human Human Poly- Mouse Poly Human Poly- Mouse Mouse Polypeptide nucleotide Polypeptide nucleotide Polypeptide nucleotide Polypeptide Polynucleotide Gene Name SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO: Gene Name SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO: F2RL 1479 1480 BAI2 O3 848 O4 05 TA10 481 482 BAI3 O6 849 O7 O8 TA11 483 484 DJ287G14 09 8SO 10 11 TA12 485 486 DRD1 12 851 13 14 TA14 487 488 DRDS 15 852 16 17 TA15 489 490 EBI2 18 853 19 2O HM74A 555 556 FLJ14454 21 854 22 23 PGR1SL 491 492 GHSR 24 855 25 26 TA7 493 494 GIPR 27 856 28 29 TA8 495 496 GLP2R 30 857 31 32 P2Y3L 497 498 499 500 GPR101 33 858 34 35 TCP10C 5O1 5O2 GPR103 36 859 37 38 GPR1O3L 503 SO4 GPR17 39 860 40 41 ORS1E1 505 515 525 535 GPR2O 42 861 43 44 OR4N4 SO6 S16 526 536 GPR21 45 862 46 47 OR51O1 507 517 527 537 GPR23 48 863 49 50 ORS1E2 SO8 S18 528 538 GPR25 51 864 52 53 OR8B3 509 519 529 539 GPR26 S4 865 55 56 OR7D2 510 52O 530 S4O GPR37L1 57 866 58 59 OR2A7 511 521 531 541 GPR39 60 867 61 62 OR7E102 512 522 532 S42 GPR4 63 868 64 65 OR2A1 513 523 533 543 GPR48 66 869 67 68 OR22 S1.4 524 534 544 GPR51 69 870 70 71 GPRS8 72 871 73 74 GPR62 75 872 76 77 GPR64 78 873 79 8O GPR68 81 874 82 83 0611) GPR82 84 875 85 86 GPR92 87 876 88 89 TABLE 2 GRM2 90 877 91 92 GRM4 93 878 94 95 Novel GPCRs GRMS 96 879 97 98 GRM6 99 880 2OO 2O1 Human GRM7 2O2 881 2O3 204 Human Poly- Mouse Mouse HCRTR1 205 882 2O6 2O7 Polypeptide nucleotide Polypeptide Polynucleotide HCRTR2 208 883 209 210 Gene Name SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO: KIAAO758 211 884 212 213 LEC1 214 885 215 216 KIAA1828 1 2 3 4 LEC2 217 886 218 219 PGR1O 5 6 7 8 LEC3 220 887 221 222 PGR11 9 10 11 12 LGR6 223 888 224 225 PGR12 13 14 15 16 LGR7 226 889 227 228 PGR13 17 18 19 2O MTNR1B 229 890 230 231 PGR14 21 22 23 24 NPFF1R 232 891 233 234 PGR15 25 26 27 28 PGR1SL 1491 1492 PGR17 29 30 31 32 RE2 237 892 238 239 PGR2 33 34 35 36 SCTR 240 893 241 242 PGR2O 37 38 39 40 SREB3 243 894 244 245 PGR22 41 42 43 44 TAR2 246 247 PGR25 45 46 47 48 TAR3 248 895 249 250 PGR26 49 50 51 52 TM7SF1L2 251 896 252 253 PGR3 53 S4 55 56 PGR5 57 58 59 60 PGR1 61 62 63 836 PGR16 64 65 66 837 Polypeptide Expression and Purification PGR18 67 68 69 838 0612 Recombinant GPCR polypeptides may be pro PGR19 70 71 72 839 PGR21 73 74 75 840 duced using standard techniques known in the art. Such PGR23 76 77 78 841 recombinant GPCR polypeptides are, for example, useful in PGR24A 79 8O in vitro assays for identifying therapeutic compounds. PGR24P 1551 1552 PGR27 81 82 83 842 0613. Accordingly, the present invention relates to PGR28 84 85 86 843 expression systems that include a polynucleotide of the PGR4 87 88 89 84.4 present invention, host cells that are genetically engineered PGR6 90 91 with Such expression systems, and production of polypep PGR7 92 93 94 845 PGR9 95 96 tides of the invention by recombinant techniques. Cell-free AGR9 97 846 98 99 translation systems can also be employed to produce Such BAI1 100 847 101 102 proteins using RNAs derived from the DNA constructs of the present invention. US 2006/0134109 A1 Jun. 22, 2006

0614 For recombinant production, host cells can be for transcription termination, and a selectable marker gene. genetically engineered to incorporate expression systems or Shuttle vectors for replication in both yeast and E. coli are portions thereof for any polynucleotide of the present inven also included herein. tion. Polynucleotides may be introduced into host cells by 0.617 Alternatively, insect cells may be used as host cells. methods described in standard laboratory manuals. Preferred In a preferred embodiment, the polypeptides of the invention methods of introducing polynucleotides into host cells are expressed using a baculovirus expression system (see, include, for instance, calcium phosphate transfection, Luckow et al., BioTechnology, 1988, 6. and Baculovirus DEAE-dextran mediated transfection, transvection, micro Expression Vectors: A Laboratory Manual, O'Rielly et al. injection, cationic lipid-mediated transfection, electropora (Eds.), W.H. Freeman and Company, New York, 1992, each tion, transduction, ballistic introduction, infection or fusion of which is incorporated herein by reference in its entirety). with carriers such as liposomes, micelles, ghost cells, and In addition, the Bac-to-BacTm complete baculovirus expres protoplasts. sion system (Invitrogen) can, for example, be used for production in insect cells. 0615. A great variety of expression systems can be used. These include, without limitation, chromosomal, episomal, 0618 Expression of proteins in prokaryotes is most often and virus-derived systems such as vector derived bacterial carried out in E. coli with vectors containing constitutive or plasmids, bacteriophage, transposons, yeast episomes, inser inducible promoters directing the expression of either fusion tion elements, yeast chromosomal elements, viruses (such as or non-fusion proteins. Fusion vectors add a number of baculoviruses, papova viruses, such as SV40, vaccinia amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion viruses, adenoviruses, fowl pox viruses, pseudorabies vectors typically serve three purposes: 1) to increase expres viruses, and retroviruses), and vectors derived from combi sion of recombinant protein; 2) to increase the solubility of nations thereof. Such as those derived from plasmid and the recombinant protein; and 3) to aid in the purification of bacteriophage genetic elements, such as cosmids and the recombinant protein by acting as a ligand in affinity phagemids. Preferred expression vectors include, but are not purification. Often, in fusion expression vectors, a pro limited to, pcDNA3 (Invitrogen) and pSVL (Pharmacia teolytic cleavage site is introduced at the junction of the Biotech). Other expression vectors include, but are not fusion moiety and the recombinant protein to enable sepa limited to, pSPORTTm vectors, pGEMTm vectors ration of the recombinant protein from the fusion moiety (Promega), pPROEXvectorsTrm (LTI, Bethesda, Md.), Blue Subsequent to purification of the fusion protein. Such ScriptTm vectors (Stratagene), pCRETm vectors (Qiagen), enzymes, and their cognate recognition sequences, include pSE420Tm (Invitrogen), and pYES2Tm(Invitrogen). The expression systems may contain control regions that regulate Factor Xa, thrombin and enterokinase. as well as engender expression. Generally, any system or 0619 Typical fusion expression vectors include pGEX vector that is able to maintain, propagate, or express a (Pharmacia Biotech Inc.; Smith, D. B. and Johnson, K. S. polynucleotide to produce a polypeptide in a host may be (1988) Gene 67:31-40), pMAL (New England Biolabs, used. The appropriate polynucleotide may be inserted into Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) an expression system by any of a variety of well-known and which fuse glutathione S-transferase (GST), maltose E bind routine techniques, including transformation, transfection, ing protein, or protein A, respectively, to the target recom electroporation, nuclear injection, or fusion with carriers binant protein. Such as liposomes, micelles, ghost cells, and protoplasts. 0620. If a polypeptide of the present invention is to be Expression systems of the invention include bacterial, yeast, expressed for use in screening assays, it maybe produced at fungal, plant, insect, invertebrate, vertebrate, and mamma the surface of the cell. In this event, the cells may be lian cells systems. harvested prior to use in the screening assay. If the polypep 0616) If a eukaryotic expression vector is employed, then tide is secreted into the medium, the medium can be recov the appropriate host cell would be any eukaryotic cell ered in order to recover and purify the polypeptide. If capable of expressing the cloned sequence. Preferably, produced intracellularly, the cells must first be lysed before eukaryotic cells are cells of higher eukaryotes. Suitable the polypeptide is recovered. eukaryotic cells include, but are not limited to, non-human 0621 Polypeptides of the present invention can be recov mammalian tissue culture cells and human tissue culture ered and purified from recombinant cell cultures by well cells. Preferred host cells include, but are not limited to, known methods including ammonium sulfate or ethanol insect cells, HeLa cells, Chinese hamster ovary cells (CHO precipitation, acid extraction, anion or cation exchange cells), African green monkey kidney cells (COS cells), chromatography, phosphocellulose chromatography, hydro human 293 cells, murine embryonal stem (ES) cells and phobic interaction chromatography, affinity chromatogra murine 3T3 fibroblasts. Propagation of such cells in cell phy, hydroxyapatite chromatography and lectin chromatog culture has become a routine procedure (see, Tissue Culture, raphy. Most preferably, high performance liquid Academic Press, Kruse and Patterson, eds. (1973), which is chromatography is employed for purification. Well-known incorporated herein by reference in its entirety). In addition, techniques for refolding proteins may be employed to regen a yeast host may be employed as a host cell. Preferred yeast cells include, but are not limited to, the genera, Saccharo erate active conformation when the polypeptide is denatured myces, Pichia, and Kluveromyces. Preferred yeast hosts are during intracellular synthesis, isolation, and/or purification. S. cerevisiae and P. pastoris. Preferred yeast vectors can 0622 Recombinant GPCR polypeptides (or alternatively, contain an origin of replication sequence from a 2T yeast GPCR polypeptides isolated from an organism) may be plasmid, an autonomously replication sequence (ARS), a targeted to the cell membrane. Membrane bound GPCR can promoter region, sequences for polyadenylation, sequences be prepared by expressing the GPCR in a suitable cell or cell US 2006/0134109 A1 Jun. 22, 2006

line, e.g., Pichia pastoris cells, oocytes, or COS cells. cloning site. In addition, the plasmid contains the DHRF Membranes containing the recombinant polypeptide may (dihydrofolate reductase) gene which provides selection in then be isolated from other cellular components by standard the presence of the drug methotrexane (MTX) for selection methods known in the art. of stable transformants. Expression of GPR 85 or Other GPCR Listed in Table 1. 0626. The forward primer is determined by routine pro cedures and preferably contains a 5' extension which intro 0623 Recombinant expression of GPR85 or other GPCR duces an Xbal restriction site for cloning, followed by encoding polynucleotide listed in Table 1 is expressed in a nucleotides which correspond to a sequence selected from Suitable host cell using a Suitable expression vector by the group consisting of sequences listed in Table 1. The standard genetic engineering techniques. For example, the reverse primer is also determined by routine procedures and GPR85 is subcloned into the commercial expression vector preferably contains 5' extension of nucleotides which intro pcDNA3.1 (Invitrogen, San Diego, Calif.) and transfected duces a restriction cloning site followed by nucleotides into Chinese Hamster Ovary (CHO) cells using the trans which correspond to the reverse complement of a sequence fection reagent FuGENE6 (Boehringer-Mannheim) and the selected from the group consisting of sequences listed in transfection protocol provided in the product insert. Other Table 1. The PCR reaction is performed as described in the eukaryotic cell lines, including human embryonic kidney manufactures instructions. The PCR product is gel purified (HEK293) and COS cells, are suitable as well. Cells stably and ligated into the p3-C1 vector. This construct is trans expressing GPCR are selected by growth in the presence of formed into E. coli cells for amplification and DNA purifi 100 ug/ml Zeocin (Stratagene, LaJolla, Calif.). Optionally, cation. The expression vector containing the GPCR poly GPR85 may be purified from the cells using standard nucleotide sequence is purified with Qiagen chromatographic techniques. To facilitate purification, anti chromatography columns and transfected into COS 7 cells sera, is raised against one or more synthetic peptide using LipofectamineTM reagent from BRL, following the sequences that correspond to portions of the GPR85 amino manufacturer's protocols. Forty-eight and 72 hours after acid sequence, and the antisera is used to affinity purify transfection, the media and the cells are tested for recom GPCR. GPR85 also may be expressed in-frame with a tag binant protein expression. GPCR expressed from a COS cell sequence (e.g., polyhistidine, hemagluttinin, FLAG) to culture can be purified by concentrating the cell-growth facilitate purification. Moreover, it will be appreciated that media to about 10 mg of protein/ml, and purifying the many of the uses for GPCR polypeptides, such as assays protein by chromatography. described below, do not require purification of GPCR from the host cell. 0627 Expression of GPCR in Insect Cells. For expres sion of GPCR in a baculovirus system, a polynucleotide 0624 Expression of GPCR in 293 cells. For expression molecule having a sequence selected from the group con of GPCR polypeptides in mammalian cells HEK293 (trans sisting of sequences listed in Table 1, can be amplified by formed human, primary embryonic kidney cells), a plasmid PCR. The forward primer is determined by routine proce bearing the relevant GPCR coding sequence is prepared dures and preferably contains a 5' extension which adds the (Table 1 ), using vector pcDNA3.1 (Invitroen). The forward Ndel cloning site, followed by nucleotides which correspond primer for amplification of this GPCR cDNA is determined to a sequence selected from the group consisting of by routine procedures and preferably contains a 5' extension sequences listed in Table 1. The reverse primer is also of nucleotides to introduce the HindIII cloning site and determined by routine procedures and preferably contains a nucleotides matching the GPCR sequence. The reverse 5' extension which introduces the KpnI cloning site, fol primer is also determined by routine procedures and pref lowed by nucleotides which correspond to the reverse erably contains a 5' extension of nucleotides to introduce an complement of a sequence selected from the group consist Xbal restriction site for cloning and nucleotides correspond ing of sequences listed in Table 1. ing to the reverse complement of the GPCR sequence. The PCR product is gel purified and cloned into the HindIII-Xbal 0628. The PCR product is gel purified, digested with sites of the vector. Ndel and Kpn, and cloned into the corresponding sites of vector p ACHTL-A (Pharmingen, San Diego, Calif.). The 0625. The expression vector containing the GPCR gene is pAcHTL-A expression vector contains the strong polyhedrin purified using Qiagen chromatography columns and trans promoter of the Autographa Californica nuclear polyhedro fected into 293 cells using DOTAPTm transfection media sis virus (AcMNPV), and a 6xHis tag upstream from the (Bochringer Mannheim, Indianapolis, Ind.). Transiently multiple cloning site. A protein kinase site for phosphory transfected cells are tested for expression after 24 hours of lation and a thrombin site for excision of the recombinant transfection, using western blots probed with anti-His and protein precede the multiple cloning site is also present. Of anti-GPCR peptide antibodies. Permanently transfected course, many other baculovirus vectors could be used in cells are selected with Zeocin and propagated. Production of place of pAcHTL-A, such as pac373, pVL941 and the recombinant protein is detected from both cells and pAcIML. Other suitable vectors for the expression of GPCR media by western blots probed with anti-His, or anti-GPCR polypeptides can be used, provided that the vector construct peptide antibodies. Expression of GPCR in COS cells. For includes appropriately located signals for transcription, expression of the GPCR in COS7 cells, a polynucleotide translation, and trafficking, such as an in-frame AUG and a molecule having a sequence selected from the group con signal peptide, as required. Such vectors are described in sisting of polynucleotide sequences listed in Table 1, can be Luckow et al., Virology 170:31-39, among others. The virus cloned into vector p3-CI. This vector is a puC18-derived is grown and isolated using standard baculovirus expression plasmid that contains the HCMV (human cytomegalovirus) methods, Such as those described in Summers et al. (A promoter-intron located upstream from the bCH (bovine Manual of Methods for Baculovirus Vectors and Insect Cell growth hormone) polyadenylation sequence and a multiple Culture Procedures, Texas Agricultural Experimental Sta US 2006/0134109 A1 Jun. 22, 2006

tion Bulletin No. 1555 (1987)); In a preferred embodiment, Subsequently to the final cycle, reactions were extended for pAcHLT-A containing a GPCR gene is introduced into 7 minutes at 72°C. All PCR products were analyzed on a 2% baculovirus using the “BaculoGoldTM transfection kit agarose gel containing ethidium bromide and visualized on (Pharmingen, San Diego, Calif.) using methods established an Alpha Imager. Scanning was performed on an Alpha by the manufacturer. Individual virus isolates are analyzed Imager by the Alpha Ease Program (Alpha Innotech). for protein production by radiolabeling infected cells with 35S-methionine at 24 hours post infection. Infected cells are 0635 Primers: Primers were designed using the Oligo 6.0 harvested at 48 hours post infection, and the labeled proteins program (Mol. Bio. Insights). Their specificity was evalu are visualized by SDS-PAGE. Viruses exhibiting high ated by BLAST searches of the human and mouse genomes expression levels can be isolated and used for scaled up and confirmed by sequencing the bands obtained from expression. RT-PCR. 0629. For expression of a GPCR polypeptide in a Sf9 In Situ Hybridization cells, a polynucleotide molecule having a sequence selected from the group consisting of sequences listed in Table 1, can 0636 Tissue dissection and sectioning: 8-10 week old be amplified by PCR using the primers and methods male 129SI/SvIMJ mice (Jackson Laboratory) were sacri described above for baculovirus expression. The GPCR ficed and their brains were dissected, Snap frozen on dry ice, cDNA is, cloned into vector p AcHLT-A (Pharmingen) for and stored at -70° C. Brains were sectioned at 10-14 um expression in Sf9 insect cells. The insert is cloned into the onto microscope slides. Sections were collected in series so Ndel and Kpnl sites, after elimination of an internal Ndel site (using the same primers described above for expression in that each gene was sampled at 100 um intervals through the baculovirus). DNA is purified with Qiagen chromatography hypothalamus and amygdala, and at 500 um intervals columns and expressed in Sf9 cells. Preliminary Western through the remainder of the brain. blot experiments from non-purified plaques are tested for the 0637 Riboprobe preparation: T3 (sense) and T7 (anti presence of the recombinant protein of the expected size sense) promoters were attached to either side of the gene of which reacted with the GPCR-specific antibody. interest and amplified by PCR, using primers with the GPCR Expression Profiles: Related Diseases and Disorders corresponding gene and promoter sequences. Transcription 0630. Expression profiles for GPCRs of the present reactions were performed using Ambion Maxiscript kits. invention were determined with human and mice tissues PCR generated templates (500 ng) were added to 100 uCi of using RT-PCR and tissue in situ hybridization methods. Our dried down P-UTP (Perkin Elmer) in 10 ul reactions. findings are Summarized below. 0638 Hybridization: Prehybridization and hybridization Methods reactions were performed as previously described, with modifications. Briefly, Plabeled riboprobes (-5x10 cpm/ RT-PCR slide) were applied to slides overnight at 55° C. Slides were 06.31 Tissue harvesting: 8-10 week old male or female then digested with RNAse and rinsed in SSC, with a final 129S 1/SVIMJ mice (Jackson Laboratory) were used for rinse in 0.1XSSC at 70° C. for 30 min. Slides were Subse tissue harvesting. Peripheral tissues were dissected fresh and quently dipped in NTB-2 emulsion, and developed after 3 stored in RNAlater at 4°C. (Ambion). Some tissues were weeks. also purchased from PelFreez and kept frozen at -80° C. until RNA extraction. Brains were removed and stored 0639 Analysis: Specific mRNA distributions were deter overnight at 4°C. in RNAlater, then microdissected under a mined by examination of two complete brains for each gene, Leica MZ6 dissecting microscope into nine regions, using with light and darkfield microscopy. An additional brain was landmarks from a mouse atlas. examined for sense labeling, to assess sites of non-specific 0632 RNA preparation: RNA was extracted using the signal. Specific signal was scored as clusters of silver grains Totally RNA kit (Ambion) including LiCl precipitation and over discrete cells or brain regions, without corresponding DNAse (Epicenter) treatment. To test for genomic DNA signal in sense slides. Sections were counterstained with contamination, intron/exon spanning PCR primers for sev cresyl Violet for contrast and regional identification. Images eral genes (ApoAI, Nurr1, Actin, G3PDH and Blue opsin) were captured with a Photometric CoolSnap camera and were used in RT-PCRs, performed in the presence or absence Universal Imaging MetaMorph software (both Meridian of RT, with 200 ng of input cDNA. Instruments). 0633 RT reactions: 5 lug of each RNA sample was Expression Profile Results reverse transcribed with random primers (Roche) in a 40 ul 0640 We have determined the expression pattern for reaction with 40U MMLV-RT (Roche) and 20U RNAse GPCRs, providing functional information for these receptors inhibitor (Roche). cDNAs were treated with RNAse H (Table 1). In addition, we have identified several new (Epicenter) and RNAse A (Ambion) and normalized with GPCRs (Table 2). The GPCR polypeptides and polynucle 18S RNA primer sets (Ambion). otides may be relevant for the treatment or diagnosis of 0634 PCRs: Gene amplification was carried out in 25 ul various disease or disorders, particularly behavioral disor reactions with 2 ng, 20 ng or 200 ng of input cDNA, in the ders. In addition to the wild-type GPCR polypeptide, poly presence of 1.25 U of AmpliTaq Gold Polymerase (Applied morphic, splice variant, mutagenzied, and recombinant Biosystems) and 0.25uM of each primer. Cycling conditions forms of a GPCR polypeptide may also be targets for were: 94° C. for 5 minutes, followed by 37 or 40 cycles of treatment or diagnosis of diseases and disorders or for 94° C./0.5 minute -65° C.A.O.5 minute -72° C./1 minute. assaying for therapeutic compounds.

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TABLE 7-continued GPCRs Expressed in the Male Brain CELSR2 FZD5 GPRS6 HTR2C PGR1O VIPR2 CELSR3 FZD6 GPR6 HTR4 PGR11 VLGR1 CHRM1 FZD7 GPR61 HTRSA PGR13 CHRM2 FZD8 GPR62 HTR6 PGR14 CHRM3 G2A GPR63 HTR7 PGR15

0646 Brainstem and midbrain. GPCRs expressed in the 0647. Cerebellum. GPCRs expressed in the cerebellum brainstem and midbrain are listed in Table 8. These receptors are listed in Table 9. These receptors are thus potential are thus potential targets for therapeutic compounds that targets for therapeutic compounds that may modulate the may modulate their activity, expression, or stability in the nervous system. These polypeptides, or polymorphs of these activity, expression, or stability of the GPCR in the cerebel polypeptides, may form the basis of a therapeutic regimen, lum. These polypeptides, or polymorphs of these polypep or a diagnostic test to determine, e.g., the presence of a tides, may form the basis of a therapeutic regimen, or a disease or disorder of the nervous system, the risk of diagnostic test to determine, e.g., the presence of disease, the developing a particular disease or disorder, or an appropriate risk of developing a particular disease or disorder, or an therapeutic course. appropriate therapeutic course.

TABLE 8 GPCRs Expressed in the Brainstem ADCYAP1R1 CMKBR1L2 GALR2 HTR4 PGR15 ADMIR CMKLR1 HSR HTRSA PGR16 ADORA1 CNR1 PR HTR6 PGR18 ADORA2A CNR2 C R HTR7 PGR2O ADORA2B CRHR1 HUMNPIIY2O PGR21 ADORA3 CRHR2 KIAAO758 PGR22 ADRA1A CX3CR1 KIAA1828 PGR23 ADRA1D CXCR4 LEC1 PGR27 ADRA2A CXCR6 LEC2 PGR28 ADRA2B CYSLT1 O 5 LEC3 PGR3 ADRB1 287G14 PGR7 ADRB2 RD1 LGR8 PPYR1 AGR9 RD2 LHCGR. PTAFR AGTR1 RD3 MAS1 PTGDR AGTR2 RDS PTGER1 AGTRL1 2 PTGER2 AVPR1A DG1 PTGER3 AVPR2 DG2 MCSR PTGER4 BAI1 DG3 MRG PTGFR BAI2 DG4 MRGE PTGIR BAI3 DGS RAI3 BDKRB1 DG6 RDC1 BDKRB2 DG7 RE2 BLR1 DG8 RREH BRS3 DNRA SALPR CSR1 DNRB SCTR CALCR R1 SMOH CALCRL L SREB3 CASR SSTR1 CCBP2 OA1 SSTR2 CCKA R OPN1MW SSTR3 CCKBR OPN3 SSTR4 CCR1 OPRD1 TACR2 CCR5 OPRK1 TACR3 CCR6 OPRL1 TEMS CCRT OPRM1 TM7SF1 CCRL1 OXTR TM7SF1L1 CD97 P2RY1 TM7SF1L2 CELSR1 P2RY12 TM7SF3 CELSR2 P2RY2 TPRA40 CELSR3 P2RY6 TRHR CHRM1 P2Y5 TRHR2 CHRM2 PR61 PGR1O TSHR CHRM3 PR62 PGR11 VIPR2 CHRM4 PR63 PGR13 VLGR1 CHRMS PR65 PGR14